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1. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

Author: Gill Wilson, Anna de Burca, Marta Bleda, Lucy R. Wedderburn, Matthew Welland, Kathleen Stirrups, Valentina Cipriani, Kerrie Woods, Vijeya Ganesan, Susan Hill, Rosaline Quinlivan, Georgia Chan, Mehul T. Dattani, Robert McFarland, Graeme C.M. Black, Rutendo Mapeta, Augusto Rendon, Francesco Muntoni, James O.J. Davies, Mina Ryten, Rebecca E. Foulger, Arianna Tucci, Dina Halai, Tom Fowler, Noemi B.A. Roy, Sarah Leigh, Dragana Josifova, Philip Twiss, Ana L.T. Tavares, Zerin Hyder, Detlef Bockenhauer, Patrick Yu-Wai-Man, Lara Abulhoul, Nikolas Pontikos, Anthony T. Moore, Huw R. Morris, Patrick F. Chinnery, Nicholas W. Wood, Ellen A. Thomas, Shehla Mohammed, Sofia Douzgou, Tanya Lam, Kate Gibson, Robert Sarkany, Teofila Bueser, Wei Wei, Siddharth Banka, Alexander Broomfield, Hiva Fassihi, Nils Koelling, Carolyn Campbell, James Buchanan, Melita Irving, Sandrine Compeyrot-Lacassagne, Karola Rehmström, Austen Worth, Nikhil Thapar, Andrew R. Webster, Paul Brennan, Rita Horvath, Gavin Arno, Richard H Scott, Sam Malka, Andrew O.M. Wilkie, Sofie Ashford, Maria Bitner-Glindzicz, Jana Vandrovcova, William G. Newman, Caroline F. Wright, Andrew M. Schaefer, Roger F.L. James, Robert W. Taylor, Melanie Babcock, Arjune Sen, Emma Baple, Ellen M. McDonagh, Stephanie Grunewald, Loukas Moutsianas, Melissa A. Haendel, Olivera Spasic-Boskovic, Eleanor G. Seaby, Anna Need, Clarissa Pilkington, Sarah Wordsworth, Shamima Rahman, Christine Patch, Colin Wallis, Kristina Ibanez, Bishoy Habib, Eik Haraldsdottir, Huw B. Thomas, Razvan Sultana, Andrea H. Németh, Agata Wolejko, Claire Palles, Phil Beales, Adam C. Shaw, Letizia Vestito, Emily Li, Sarah Rose, Sarah Hunter, Angela Matchan, Genevieve Say, Dalia Kasperaviciute, Henry Houlden, Raymond T. O’Keefe, R. Andres Floto, Jill Clayton-Smith, John B. Taylor, Hywel J. Williams, Volker Straub, Val Davison, Helen Savage, John Chisholm, Eleanor Dewhurst, Charles Crichton, Andrea Haworth, Clare Turnbull, Carolyn Tregidgo, Carme Camps, Christopher Penkett, Emer O’Connor, Georgina Hall, Lyn S. Chitty, Sally Halsall, Andrew D. Mumford, Annette G. Wagner, Eleanor Williams, Mark Bale, Julius O. Jacobsen, Willem H. Ouwehand, Charu Deshpande, Gavin Burns, Smita Y. Patel, James Polke, Thiloka Ratnaike, Gavin Fuller, John Burn, Kenneth E. S. Poole, Emma Footitt, John R. Bradley, Suzanne Wood, Russell J. Grocock, Jenny C. Taylor, Louise Izatt, Kikkeri N. Naresh, Katherine R. Smith, Nigel Burrows, Katrina Newland, Peter N. Robinson, Sarju G. Mehta, Michael A. Simpson, Michael R. Barnes, Pilar Cacheiro, Olivia Niblock, Tracy Lester, Dimitris Polychronopoulos, Helen Brittain, John A. Sayer, Antonio Martin, Eshika Haque, Sean Humphray, Douglass M. Turnbull, Damian Smedley, Andrew Devereau, Stefan Gräf, Sian Ellard, Ivone U.S. Leong, Martin G. Reese, Matthias Wielscher, Louise C. Daugherty, Perry M. Elliott, F. Lucy Raymond, Cecilia Compton, David Bentley, Catherine Snow, James Welch, Frances Flinter, Dom McMullan, Mark J. Caulfield, Paul Aurora, Mark Gurnell, Mary Kasanicki, I. Karen Temple, Michel Michaelides, Deborah Ruddy, Leema Robert, Janice Yip, Grainne S. Gorman, Andrew C. Browning, Richard Quinton, Maureen Cleary, Jamie M. Ellingford, Angela Douglas, Christopher Boustred, and Investigators, The 100,000 Genomes Project Pilot
Subjects: Adult, Male, Proband, medicine.medical_specialty, Adolescent, Pilot Projects, Genomics, Polymerase Chain Reaction, Genome, State Medicine, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Health care, Human Phenotype Ontology, Humans, Medicine, Child, Exome sequencing, 030304 developmental biology, Family Characteristics, 0303 health sciences, Whole Genome Sequencing, Genome, Human, business.industry, Genetic Variation, Rare Diseases/diagnosis, General Medicine, Middle Aged, United Kingdom, 3. Good health, Child, Preschool, Family medicine, Medical genetics, Female, business, Bristol, 030217 neurology & neurosurgery, Rare disease
Abstract: BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).
Published: 2021
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2. Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease

Author: Kyle Thompson, Xiao-Long Zhou, Flemming Wibrand, Wen-Qiang Zheng, Julie Vogt, Daria Diodato, Lucy Raymond, Anja Ernst, Robert W. Taylor, Emanuele Bellacchio, Rita Horvath, Jakob Ek, Benjamin Munro, Manali Chitre, Dorothy K. Grange, Tue Diemer, Elsebet Østergaard, Courtney E. French, Toni S. Pearson, and Signe Vandal Pedersen
Subjects: Mitochondrial encephalomyopathy, Mitochondrial Diseases, Mitochondrial translation, media_common.quotation_subject, Mitochondrial disease, Nonsense, Population, Biology, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Mitochondrial Encephalomyopathies, Threonine-tRNA Ligase, Genetics, medicine, Humans, Missense mutation, education, Molecular Biology, Genetics (clinical), 030304 developmental biology, media_common, RNA, Transfer, Thr, Dystonia, 0303 health sciences, education.field_of_study, General Medicine, medicine.disease, Phenotype, Mutation, 030217 neurology & neurosurgery
Abstract: TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. In addition, we document seven novel TARS2 variants—one nonsense variant and six missense variants—that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modeling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.
Published: 2021
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3. Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy

Author: Chinthana Thangavel, Gavin Arno, Renae Elaine Bertrand, Rui Chen, Anthony G. Robson, Renata T Simões, Qingnan Liang, Jun Wang, Kaitlyn H. Xiong, Fernanda Belga Ottoni Porto, Xinye Qian, Rola Ba-Abbad, Keren J. Carss, F. Lucy Raymond, Andrew R. Webster, and Shirley Aparecida Madureira Sampaio
Subjects: 0301 basic medicine, Retinal degeneration, Ceramide, genetic structures, 030105 genetics & heredity, Biology, Article, Retina, Photoreceptor cell, Mice, 03 medical and health sciences, chemistry.chemical_compound, Retinal Dystrophies, Electroretinography, medicine, Animals, Humans, Outer nuclear layer, Ceramide synthase, Genetics (clinical), cone-rod degeneration, medicine.diagnostic_test, Retinal Degeneration, Dystrophy, medicine.disease, novel disease gene, TLCD3B, eye diseases, Cell biology, ceramide synthase, 030104 developmental biology, medicine.anatomical_structure, chemistry, Retinal Cone Photoreceptor Cells, sense organs, Oxidoreductases
Abstract: Purpose Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration. Methods Exome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses. Results Here we have identified four patients with cone-rod dystrophy or maculopathy from three families carrying pathogenic variants in TLCD3B. Consistent with the phenotype observed in patients, the Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina. Conclusion Our results provide the first link between loss-of-function variants in a ceramide synthase gene and human retinal dystrophy. Establishment of the Tlcd3b knockout murine model, the first in vivo photoreceptor cell degeneration model due to loss of a ceramide synthase, will provide a unique opportunity in probing the role of ceramide in survival and function of photoreceptor cells.
Published: 2021
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4. Recommendations for designing genetic test reports to be understood by patients and non-specialists

Author: F. Lucy Raymond, George D. Farmer, Harry Gray, Alexandra L. J. Freeman, Gemma Chandratillake, Farmer, George D [0000-0003-2882-0310], Gray, Harry [0000-0002-6714-0089], Freeman, Alexandra LJ [0000-0002-4115-161X], Apollo - University of Cambridge Repository, Farmer, George D. [0000-0003-2882-0310], and Freeman, Alexandra L. J. [0000-0002-4115-161X]
Subjects: Research Report, Patients, Genetic Counseling, Computer-assisted web interviewing, 03 medical and health sciences, Human behaviour, 692/700/1719, Genetics, Humans, Genetic Testing, Set (psychology), Genetics (clinical), 030304 developmental biology, 0303 health sciences, Medical education, business.industry, 706/689/477/2811, 030305 genetics & heredity, article, Foundation (evidence), Patient education, Medical Writing, 3. Good health, Test (assessment), Variety (cybernetics), Comprehension, Practice Guidelines as Topic, Personalized medicine, Psychology, business, Inclusion (education)
Abstract: Patients and non-specialist healthcare professionals are increasingly expected to understand and interpret the results of genetic or genomic testing. These results are currently reported using a variety of templates, containing different amounts, levels, and layouts of information. We set out to establish a set of recommendations for communicating genetic test results to non-expert readers. We employed a qualitative-descriptive study design with user-centred design principles, including a mixture of in-person semi-structured interviews and online questionnaires with patients, healthcare professionals and the general public. The resulting recommendations and example template include providing at-a-glance comprehension of what the test results mean for the patient; suggested next steps; and details of further information and support. Separation and inclusion of technical methodological details enhances non-specialists’ understanding, while retaining important information for specialists and the patients’ records. The recommendations address the high-level needs of patients and their non-specialist clinicians when receiving genetic test results. These recommendations provide a solid foundation for the major content and structure of reports, and we recommend further engagement with patients and clinicians to tailor reports to specific types of test and results.
Published: 2020
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5. Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data

Author: Zoya Kingsbury, Andrew J. Connell, Ryan J. Taft, Alba Sanchis-Juan, Courtney E. French, Matthew E.R. Butchbach, David R. Bentley, Aditi Chawla, Xiao Chen, Isabelle Delon, Michael A. Eberle, Aaron L. Halpern, F Lucy Raymond, and Nihr BioResource
Subjects: 0301 basic medicine, spinal muscular atrophy (SMA), medicine.medical_specialty, Copy number analysis, Genomics, carrier screening, SMN1, Computational biology, 030105 genetics & heredity, Biology, Genome, DNA sequencing, Article, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Child, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Base Sequence, genome sequencing (GS), Spinal muscular atrophy, bioinformatics, SMA, medicine.disease, Survival of Motor Neuron 1 Protein, nervous system diseases, 030104 developmental biology, copy-number analysis, Child, Preschool, Medical genetics, 030217 neurology & neurosurgery, Reference genome
Abstract: PurposeSpinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by the American College of Medical Genetics.MethodsWe developed a method that accurately identifies the CN of SMN1 and SMN2 using genome sequencing (GS) data by analyzing read depth and eight informative reference genome differences between SMN1/2.ResultsWe characterized SMN1/2 in 12,747 genomes, identified 1568 samples with SMN1 gains or losses and 6615 samples with SMN2 gains or losses and calculated a pan-ethnic carrier frequency of 2%, consistent with previous studies. Additionally, 99.8% of our SMN1 and 99.7% of SMN2 CN calls agreed with orthogonal methods, with a recall of 100% for SMA and 97.8% for carriers, and a precision of 100% for both SMA and carriers.ConclusionThis SMN copy number caller can be used to identify both carrier and affected status of SMA, enabling SMA testing to be offered as a comprehensive test in neonatal care and an accurate carrier screening tool in GS sequencing projects.
Published: 2020
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6. Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa

Author: Michel Michaelides, Michael E. Cheetham, Marco Aben, Alison J. Hardcastle, Hannie Kremer, Daniele Ottaviani, Stefan Mundlos, Graeme C.M. Black, Susan M Downes, Robert K. Koenekoop, Julio C. Corral-Serrano, Jordi Corominas, Gavin Arno, Andrew R. Webster, Claire E. L. Smith, Uirá Souto Melo, Carlo Rivolta, Suzanne E. de Bruijn, Chris F. Inglehearn, Raj Ramesar, L. Ingeborgh van den Born, Susanne Roosing, Christian Gilissen, Nikolas Pontikos, Musa M. Mhlanga, Jacquie Greenberg, F. Lucy Raymond, Frans P.M. Cremers, Alessia Fiorentino, Timo W. F. Mulders, Stephanie Fanucchi, Silvia Albert, Simon Mead, Lisa Roberts, Michalis Georgiou, George Rebello, Carel B. Hoyng, and Repositório da Universidade de Lisboa
Subjects: Male, Gene Expression, Enhancer RNAs, Stem cells, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Cohort Studies, chemistry.chemical_compound, Hi-C, Induced pluripotent stem cell, Child, Genetics (clinical), Genes, Dominant, 0303 health sciences, Genome, 030305 genetics & heredity, Chromosome Mapping, Nuclear Proteins, Cell Differentiation, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Cellular Reprogramming, Cell biology, Organoids, Enhancer Elements, Genetic, Ectopic expression, Retinal Cone Photoreceptor Cells, Photoreceptor precursors cells, Female, Dominant retinitis pigmentosa, Topologically associated domains, Retinitis Pigmentosa, Human, dominant retinitis pigmentosa, ectopic expression, GDPD, photoreceptor precursors cells, retinal organoids, RP17, stem cells, structural variants, topologically associated domains, whole-genome sequencing, Adult, Amino Acid Sequence, Chromosomes, Human, Pair 17, Fibroblasts, Genome, Human, Humans, Induced Pluripotent Stem Cells, Phosphoric Diester Hydrolases, Polymorphism, Genetic, Primary Cell Culture, Transcription Factors, Whole Genome Sequencing, Enhancer Elements, Biology, Chromosomes, Article, 03 medical and health sciences, Genetic, Retinitis pigmentosa, Genetics, medicine, Dominant, Polymorphism, Enhancer, Gene, Transcription factor, 030304 developmental biology, Whole-genome sequencing, Pair 17, Retinal organoids, Retinal, Cell Biology, medicine.disease, chemistry, Genes, Structural variants
Abstract: © 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.
Published: 2020

7. A Novel ATRX Mutation Presenting with Intellectual Disability and Severe Kyphoscoliosis

Author: Şule Altıner and Lucy Raymond
Subjects: Adult, Male, 0301 basic medicine, X-linked Nuclear Protein, Pediatrics, medicine.medical_specialty, Skeletal anomalies, 030105 genetics & heredity, Pathology and Forensic Medicine, 03 medical and health sciences, Facial dysmorphism, 0302 clinical medicine, alpha-Thalassemia, Intellectual Disability, Intellectual disability, medicine, Humans, Missense mutation, Kyphoscoliosis, ATRX, 030219 obstetrics & reproductive medicine, business.industry, DNA Helicases, Nuclear Proteins, General Medicine, medicine.disease, Facial appearance, Phenotype, Mutation, Pediatrics, Perinatology and Child Health, Mutation (genetic algorithm), Mental Retardation, X-Linked, business
Abstract: Background: ATR-X syndrome is an X-linked clinical condition usually associated with profound intellectual disability, facial dysmorphism and alpha-thalassemia. The syndrome is clinically heterogeneous with a broad phenotypic spectrum. Although, alpha-thalassaemia is commonly present, it may not manifest in some patients.Case report: A novel missence mutation (NM_000489: ATRX; c.6130C > T; p.Leu2044Phe) was detected in the ATR-X gene in two male siblings with severe intellectual disability, dysmorphic facial appearance and skeletal anomalies. Severe kyphoscoliosis was the main finding. Hematologic findings, one of the well-known clinical entities, were not present.Conclusion: The missense mutation we have described in our patients has not been previously reported. This finding enriches mutation spectrum of ATRX (OMIM #300032) gene. This missense mutation, which is associated with ID and kyphoscoliosis and without alpha-thalassemia, contributes to genotype-phenotype correlation of the ATR-X spectrum. This case report provides further evidence that reverse genetics is a useful approach in diagnostic process of syndromic patients in adulthood.
Published: 2019
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8. Delineating the expanding phenotype associated with SCAPER gene mutation

Author: Anthony G. Robson, Claire G. Salter, James Fasham, Gaurav V. Harlalka, Olivia Wenger, Amelia Lane, F. Lucy Raymond, Sarah Hull, Rui Chen, Emma L. Baple, Lynn Schema, Gavin Arno, Mingchu Xu, Anthony T. Moore, Andrew R. Webster, Siying Lin, Michael E. Cheetham, Timothy J. Moss, Keren J. Carss, Jay E. Self, and Andrew H. Crosby
Subjects: 0303 health sciences, Philosophy, Brachydactyly, 030305 genetics & heredity, Intellectual disability, Gene mutation, Research Letters, 3. Good health, Retinitis pigmentosa, 03 medical and health sciences, Research Letter, Genetics, Theology, SCAPER, CCNA2–CDK2, Genetics (clinical), 030304 developmental biology
Abstract: Author(s): Fasham, James; Arno, Gavin; Lin, Siying; Xu, Mingchu; Carss, Keren J; Hull, Sarah; Lane, Amelia; Robson, Anthony G; Wenger, Olivia; Self, Jay E; Harlalka, Gaurav V; Salter, Claire G; Schema, Lynn; Moss, Timothy J; Cheetham, Michael E; Moore, Anthony T; Raymond, F Lucy; Chen, Rui; Baple, Emma L; Webster, Andrew R; Crosby, Andrew H; NIHR Bioresource Rare Diseases Consortium
Published: 2019
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9. Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy

Author: F. Lucy Raymond, Hanne Irene Jensen, Ambreen Kalhoro, Raquel S. Silva, Sabine Defoort-Dhellemmes, Keren J. Carss, Valentina Cipriani, Andrew R. Webster, Claire Marie Dhaenens, Bernard Puech, Gavin Arno, Thomas Rosenberg, Nikolas Pontikos, Anthony T. Moore, and Veronica van Heyningen
Subjects: Adult, Proband, Locus (genetics), Biology, 03 medical and health sciences, Retinal Dystrophies, Genetics, Humans, Genetic Predisposition to Disease, Gene, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, Corneal Dystrophies, Hereditary, Whole genome sequencing, 0303 health sciences, Whole Genome Sequencing, Progressive bifocal chorioretinal atrophy, 030305 genetics & heredity, Haplotype, Computational Biology, Histone-Lysine N-Methyltransferase, Macular dystrophy, Pedigree, Haplotypes, Genetic Loci, Multigene Family, Female, 5' Untranslated Regions, Transcription Factors
Abstract: The autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) disease locus has been mapped to chromosome 6q14–16.2 which overlaps the North Carolina Macular Dystrophy (NCMD) locus MCDR1. NCMD is a non‐progressive developmental macular dystrophy, in which variants upstream of PRDM13 have been implicated. Whole genome sequencing was performed to interrogate structural variants (SVs) and single nucleotide variants (SNVs) in eight individuals, six affected individuals from two families with PBCRA and two individuals from an additional family with a related developmental macular dystrophy. A SNV (chr6:100,046,804 T > C), located 7.8 kb upstream of the PRDM13 gene, was shared by all PBCRA‐affected individuals in the disease locus. Haplotype analysis suggested that the variant arose independently in the two families. The two affected individuals from family 3, were screened for rare variants in the PBCRA and NCMD loci. This revealed a de novo variant in the proband, 21 bp from the first SNV (chr6:100,046,783 A > C). This study expands the non‐coding variant spectrum upstream of PRDM13 and suggests altered spatio‐temporal expression of PRDM13 as a candidate disease mechanism in the phenotypically distinct but related conditions, NCMD and PBCRA.
Published: 2019
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10. Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides

Author: Gavin Arno, Bernhard H. F. Weber, Carel B. Hoyng, L. Ingeborgh van den Born, Nathalie M. Bax, Silvia Albert, Frans P.M. Cremers, Keren J. Carss, Stéphanie S. Cornelis, Felix Grassmann, Caroline C W Klaver, F. Lucy Raymond, Mubeen Khan, Ana Fakin, Andrew R. Webster, Muhammad Imran Khan, Claire Marie Dhaenens, Riccardo Sangermano, Elfride De Baere, Sarah Naessens, Heidi Stöhr, Rob W.J. Collin, Alberta A H J Thiadens, Jan Willem R. Pott, Esmee H. Runhart, Miriam Bauwens, Bernard Puech, Isabelle Meunier, Joke B. G. M. Verheij, Alejandro Garanto, Ophthalmology, and Epidemiology
Subjects: 0301 basic medicine, antisense oligonucleotide, 030105 genetics & heredity, ABCA4, Exon, Missing heritability problem, Medicine and Health Sciences, Protein Isoforms, Genetics(clinical), Child, Genetics (clinical), Exome sequencing, POPULATION, Genetics, education.field_of_study, Exons, Middle Aged, 3. Good health, Pedigree, Stargardt disease, RNA splicing, Adult, Adolescent, RNA Splicing, Population, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, REVEALS, medicine, Humans, splice, education, Gene, Aged, MUTATIONS, deep-intronic variant, Biology and Life Sciences, IN-VITRO, Oligonucleotides, Antisense, medicine.disease, GENE, Introns, 030104 developmental biology, HEK293 Cells, Mutation, missing heritability, ATP-Binding Cassette Transporters
Abstract: Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability.Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.
Published: 2019

11. Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature

Author: Anthony T. Moore, Yann Nadjar, Miodrag Vojcic, Patrick Yu-Wai-Man, F. Lucy Raymond, James Acheson, Anthony G. Robson, Guy Lenaers, Mary M. Reilly, Neringa Jurkute, Andrew R. Webster, Jenny Higgs, Gavin Arno, Priya D. Shanmugarajah, Marios Hadjivassiliou, Valérie Touitou, Iain Horrocks, Roy Poh, University College of London [London] (UCL), NHS Foundation Trust [London], The Royal Marsden, Royal Hallamshire Hospital, Liverpool Women's NHS Foundation Trust, Royal Victoria Infirmary, Newcastle upon Tyne, Royal Hospital for Sick Children, Glasgow, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Ophtalmologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UCL, Institute of Neurology [London], University of Cambridge [UK] (CAM), Institute of Neurology, Queen Square, London, University of California (UC), HAL-SU, Gestionnaire, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), University of California, and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)
Subjects: 0301 basic medicine, Retinal degeneration, Adult, Male, Adolescent, Mutation, Missense, Visual Acuity, Disease, Retina, syndromic optic neuropathy, 03 medical and health sciences, ferredoxin reductase, Young Adult, 0302 clinical medicine, Atrophy, Retinal Dystrophies, Exome Sequencing, medicine, Genetics, Electroretinography, Missense mutation, Humans, retinal dystrophy, Child, Exome sequencing, Retrospective Studies, Whole genome sequencing, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Haplotype, medicine.disease, 3. Good health, Pedigree, Ferredoxin-NADP Reductase, 030104 developmental biology, Phenotype, FDXR, iron accumulation, Child, Preschool, Female, business, neurodegenerative disorder, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Author(s): Jurkute, Neringa; Shanmugarajah, Priya D; Hadjivassiliou, Marios; Higgs, Jenny; Vojcic, Miodrag; Horrocks, Iain; Nadjar, Yann; Touitou, Valerie; Lenaers, Guy; Poh, Roy; Acheson, James; Robson, Anthony G; Raymond, F Lucy; Reilly, Mary M; Yu-Wai-Man, Patrick; Moore, Anthony T; Webster, Andrew R; Arno, Gavin; Genomics England Research Consortium | Abstract: PurposeThe purpose of this study was to report retinal dystrophy as a novel clinical feature and expand the ocular phenotype in patients harboring biallelic candidate FDXR variants.MethodsPatients carrying biallelic candidate FDXR variants were identified by whole genome sequencing (WGS) as part of the National Institute for Health Research BioResource rare-disease and the UK's 100,000 Genomes Project (100KGP) with an additional case identified by exome sequencing. Retrospective clinical data were collected from the medical records. Haplotype reconstruction was performed in families harboring the same missense variant.ResultsTen individuals from 8 unrelated families with biallelic candidate variants in FDXR were identified. In addition to bilateral optic atrophy and variable extra-ocular findings, 7 of 10 individuals manifested retinal dystrophy comprising dysfunction and degeneration of both rod and cone photoreceptors. Five of 10 subjects had sensorineural hearing loss. The previously unreported missense variant (c.1115C g A, p.(Pro372His)) was found in 5 of 8 (62.5%) study families. Haplotype reconstruction using WGS data demonstrated a likely ancestral haplotype.ConclusionsFDXR-associated disease is a phenotypically heterogeneous disorder with retinal dystrophy being a major clinical feature observed in this cohort. In addition, we hypothesize that a number of factors are likely to drive the pathogenesis of optic atrophy, retinal degeneration, and perhaps the associated systemic manifestations.
Published: 2021
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12. RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood

Author: Nathalie Bednarek, Hannah Stamberger, Anna Basu, Diane Doummar, Walid Fazeli, Sara Zagaglia, Rikke S. Møller, F. Lucy Raymond, S. Krithika, Andrew A Mallick, Tobias Bartolomaeus, Trine Bjørg Hammer, Sarah Weckhuysen, Manju A. Kurian, J. Helen Cross, Bryan Lynch, Alba Sanchis-Juan, Laura Hernandez-Hernandez, Sanjay M. Sisodiya, Helena Martins Custodio, Anirban Majumdar, Cyril Mignot, Dora Steel, Robert Spaull, Mary D. King, Aikaterini Vezyroglou, Kathleen M. Gorman, Boris Keren, Centre de Recherche en Sciences et Technologies de l'Information et de la Communication - EA 3804 (CRESTIC), and Université de Reims Champagne-Ardenne (URCA)
Subjects: 0301 basic medicine, Dystonia, Pediatrics, medicine.medical_specialty, Ataxia, business.industry, Alternating hemiplegia of childhood, medicine.disease, Article, 3. Good health, 03 medical and health sciences, Epilepsy, 030104 developmental biology, 0302 clinical medicine, ATP1A3, Intellectual disability, medicine, Missense mutation, Human medicine, Neurology (clinical), Young adult, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: ObjectiveTo explore the phenotypic spectrum of RHOBTB2-related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals.MethodsIndividuals with RHOBTB2-related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review.ResultsEleven affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in ATP1A3, these events were reported later only in RHOBTB2 mutation–positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients.ConclusionAlthough heterozygous RHOBTB2 mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations.
Published: 2021
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13. The psychiatric phenotypes of 1q21 distal deletion and duplication

Author: Jeremy Hall, David Skuse, Ffion Evans, Anne M. Maillard, Michael John Owen, F. Lucy Raymond, David Edmund Johannes Linden, Lee Anne Green-Snyder, Thomas M. Lancaster, Sébastien Jacquemont, Samuel J.R.A. Chawner, Stefanie C. Linden, Nigel Williams, Jacqueline Smith, Marianne Bernadette van den Bree, Cameron Watson, Wendy K. Chung, Linden, Stefanie C. [0000-0003-2120-3811], Watson, Cameron J. [0000-0003-2346-4636], Smith, Jacqueline [0000-0002-2191-5571], Chawner, Samuel J. R. A. [0000-0002-2590-2874], Skuse, David [0000-0002-7891-5732], Owen, Michael J. [0000-0003-4798-0862], Maillard, Anne M. [0000-0002-4811-0693], Jacquemont, Sébastien [0000-0001-6838-8767], van den Bree, Marianne B. M. [0000-0002-4426-3254], Apollo - University of Cambridge Repository, Linden, Stefanie C [0000-0003-2120-3811], Watson, Cameron J [0000-0003-2346-4636], Chawner, Samuel JRA [0000-0002-2590-2874], Owen, Michael J [0000-0003-4798-0862], Maillard, Anne M [0000-0002-4811-0693], van den Bree, Marianne BM [0000-0002-4426-3254], RS: CAPHRI - R4 - Health Inequities and Societal Participation, Metamedica, School for Mental Health & Neuroscience, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, RS: MHeNs - R2 - Mental Health, and RS: MHeNs - R3 - Neuroscience
Subjects: Adult, Proband, medicine.medical_specialty, DNA Copy Number Variations, 45/61, Article, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Intellectual Disability, Intellectual disability, Gene duplication, medicine, Humans, Copy-number variation, Clinical genetics, Child, Psychiatry, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 692/699/476, 030304 developmental biology, Genetic testing, 0303 health sciences, medicine.diagnostic_test, 692/420/2489, 45, business.industry, medicine.disease, Anxiety Disorders, humanities, 3. Good health, Psychiatry and Mental health, Phenotype, Neurodevelopmental Disorders, Schizophrenia, Anxiety, Chromosome Deletion, medicine.symptom, business, Psychiatric disorders, 030217 neurology & neurosurgery, Psychopathology
Abstract: Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4–40.1)], 55% for duplication carriers [8.3 (1.4–55.5)]) and anxiety disorders (24% [1.8 (0.4–8.4)] and 55% [10.0 (1.9–71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.
Published: 2021

14. Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability

Author: Catherine M. Abbott, Mihail Halachev, Detelina Grozeva, Hugues Roest Crollius, F. Lucy Raymond, James Prendergast, Peter C. Kind, Hemant Bengani, Jacqueline K. Rainger, Laura C. Murphy, Liusaidh J Owen, Veronica van Heyningen, Adam Jackson, Lambert Moyon, Graeme R. Grimes, Olivera Spasic-Boskovic, Magali Naville, Emily K. Osterweil, Jilly Hope, David R. FitzPatrick, Shipra Bhatia, Susana R. Louros, MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Edinburgh, University of Cambridge [UK] (CAM), Cardiff University, Cambridge University Hospitals NHS Foundation Trust, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Grozeva, Detelina [0000-0003-3239-8415], Moyon, Lambert [0000-0003-2390-3942], Bhatia, Shipra [0000-0002-2091-7858], Louros, Susana R. [0000-0002-1012-0386], Jackson, Adam [0000-0002-3554-6682], Prendergast, James G. [0000-0001-8916-018X], Owen, Liusaidh J. [0000-0003-0363-1775], Naville, Magali [0000-0002-6821-2427], Grimes, Graeme [0000-0002-3106-5996], Halachev, Mihail [0000-0002-4594-4588], Murphy, Laura C. [0000-0003-0029-0434], Spasic-Boskovic, Olivera [0000-0003-1583-8132], van Heyningen, Veronica [0000-0003-0359-0141], Abbott, Catherine M. [0000-0001-8794-7173], Osterweil, Emily [0000-0003-0582-2284], FitzPatrick, David R. [0000-0003-4861-969X], Apollo - University of Cambridge Repository, Louros, Susana R [0000-0002-1012-0386], Prendergast, James G [0000-0001-8916-018X], Owen, Liusaidh J [0000-0003-0363-1775], Murphy, Laura C [0000-0003-0029-0434], Abbott, Catherine M [0000-0001-8794-7173], and FitzPatrick, David R [0000-0003-4861-969X]
Subjects: Male, Embryology, Embryo, Nonmammalian, X-linked intellectual disability, medicine.disease_cause, Hippocampus, Midbrain, Animals, Genetically Modified, Cohort Studies, Fragile X Mental Retardation Protein, Mice, 0302 clinical medicine, Gene Frequency, Genes, X-Linked, Medicine and Health Sciences, Exome, Regulatory Elements, Transcriptional, Zebrafish, X chromosome, Genetics, 0303 health sciences, education.field_of_study, Mutation, Mammalian Genomics, Multidisciplinary, Eukaryota, Brain, Chromosome Mapping, Tenascin, Animal Models, Genomics, Pedigree, Phenotype, Experimental Organism Systems, Osteichthyes, Vertebrates, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Anatomy, Brainstem, Research Article, Genotype, Science, Population, Mouse Models, Nerve Tissue Proteins, Biology, Research and Analysis Methods, 03 medical and health sciences, Model Organisms, medicine, Animals, Humans, Allele, education, Gene, Alleles, 030304 developmental biology, Whole genome sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genome, Human, Embryos, Organisms, Biology and Life Sciences, medicine.disease, FMR1, Disease Models, Animal, Fish, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Animal Genomics, Genetic Loci, Animal Studies, Mental Retardation, X-Linked, Zoology, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Funder: BBSRC studentship, Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.
Published: 2021
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15. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author: Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences
Subjects: 0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract: Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Published: 2020
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16. DNAJC6 mutations disrupt dopamine homeostasis in juvenile parkinsonism-dystonia

Author: Esther Meyer, Christian de Goede, Manju A. Kurian, Sniya Sudhakar, Barbara Csányi, Helen Coutts, Lucia Abela, Simon Heales, Joanne Ng, Sandeep Jayawant, Detelina Grozeva, Karl Rakshi, Angels García-Cazorla, Belén Pérez‐Dueñas, K.M. Gorman, Lorenzo Biassoni, John Cain, Toni S. Pearson, F. Lucy Raymond, Elisenda Cortès-Saladelafont, Deborah Hughes, Rosalind J. Jefferson, Kshitij Mankad, Pichet Termsarasab, and Simon Pope
Subjects: 0301 basic medicine, Movement disorders, parkinsonism, DNAJC6, Dopamine, Auxilin, Regular Issue Articles, Bioinformatics, dopamine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Parkinsonian Disorders, Medicine, Homeostasis, Humans, Neurotransmitter, Child, Research Articles, Dystonia, auxilin, business.industry, Parkinsonism, Neurodegeneration, Dopaminergic, dystonia, HSP40 Heat-Shock Proteins, medicine.disease, 030104 developmental biology, Neurology, chemistry, Mutation, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug, Research Article
Abstract: BACKGROUND: Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin-mediated endocytosis (CME), as in DNAJC6-related juvenile parkinsonism. OBJECTIVE: To report on a new patient cohort with juvenile-onset DNAJC6 parkinsonism-dystonia and determine the functional consequences on auxilin and dopamine homeostasis. METHODS: Twenty-five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole-exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G-associated kinase and synaptic proteins. RESULTS: We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. (123) I-FP-CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G-associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced. CONCLUSIONS: DNAJC6 is an emerging cause of recessive juvenile parkinsonism-dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G-associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G-associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism-dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Published: 2020

17. De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Author: Katy Barwick, F. Lucy Raymond, Pia Zacher, Saskia B. Wortmann, Koen L.I. van Gassen, Michaela Bonfert, Bernt Popp, Eva H. Brilstra, Marie-José van den Bogaard, Alyssa Gates, Johan Lundgren, Dewi P. Bakker, Ashley C. Taylor, Alba Sanchis-Juan, Rikke S. Møller, Jessica Van Ziffle, Matias Wagner, Anne Slavotinek, Heather C Mefford, Heinrich Sticht, Joseph T. Shieh, Manju A. Kurian, Marwan Shinawi, Patrick Devine, Boris Keren, Konrad Platzer, Gabriella Horvath, Jennifer Keller-Ramey, Kathleen A. Leppig, Nicholas Stong, Alexandrea Wadley, Tomi L. Toler, Julian R. Sampson, Richard H. van Jaarsveld, Caroline Nava, Saskia N. van der Crabben, Jennifer Friedman, Mohamad A. Mikati, Marie T. McDonald, Vandana Shashi, Angus John Clarke, Wendy K. Chung, Amy McTague, Johannes R. Lemke, Tommy Stödberg, Jennifer A. Sullivan, Chiara Klöckner, Virgina Lee, and Cyril Mignot
Subjects: 0303 health sciences, Movement disorders, business.industry, Cortical visual impairment, medicine.disease, Bioinformatics, Phenotype, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Atrophy, Intellectual disability, Medicine, STXBP1, Missense mutation, medicine.symptom, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: PurposeThis study aims to provide the first comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25- DEE) by reviewing newly identified and previously reported individuals.MethodsIndividuals harboring heterozygous missense or truncating variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms and literature review. For each individual, detailed phenotyping, classification and structural modeling of the identified variant was performed.ResultsThe cohort comprises 20 individuals with (likely) pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cortical visual impairment and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.ConclusionWe provide a first comprehensive description of SNAP25-DEE with intellectual disability and early onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1 or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed “SNAREopathies”.
Published: 2020
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18. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay

Author: Paul Kruszka, Sreehari Kalvakuri, Austin Larson, Dong Li, Inge van Outersterp, Florence Demurger, Ian Hayes, F. Lucy Raymond, Lauren J. Massingham, Claudia A. L. Ruivenkamp, Ian D. Krantz, Kendra Brunet, Nicole Revencu, Maaike Vreeburg, Donatella Milani, Tjitske Kleefstra, Lisenka E.L.M. Vissers, Maximilian Muenke, Sinje Geuer, Candace Gamble, Rolf Bodmer, Hanka Venselaar, Elke de Boer, Sarina G. Kant, Dilys Weijers, Arjan P.M. de Brouwer, Machteld M. Oud, Maria Iascone, Christopher C. Griffith, Frédéric Tran Mau-Them, Karin Weiss, Megan T. Cho, Ayesha Ahmad, James A. Bartley, Nina Powell Hamilton, Lenika De Simone, George E. Hoganson, Lucie Evenepoel, Simone Kersten, Daniel L. Polla, Himanshu Goel, Antonio Vitobello, Rachel Fisher, Arthur Sorlin, Sébastien Moutton, Myrthe van den Born, Hilary J. Vernon, Michael Kwint, Kaitlyn Burns, Anna Ruiz, Kirsty McWalter, Jenny Morton, Jennifer Schwab, Elizabeth J. Bhoj, Philippe Christophe, Hans van Bokhoven, Elisabeth Gabau, Kimberly M. Nugent, Jill R. Murrell, Thierry Billette de Villemeur, Kathleen Wood, Alexandra Afenjar, Amber Begtrup, Chanika Phornphutkul, Sarah E. Raible, Melde Witmond, Perrine Charles, Claudia Soler-Alfonso, D. Isum Ward, Marjolaine Willems, Boris Keren, Julian Delanne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Clinical Genetics, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Polikliniek (9)
Subjects: Male, DYRK1A, Developmental Disabilities, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Gene Expression, de novo mutations, Haploinsufficiency, 0302 clinical medicine, Gene expression, Nuclear Receptor Subfamily 4, Group A, Member 2, Genetics (clinical), Genetics, 0303 health sciences, Gene knockdown, repressor, neurodevelopment, Protein Stability, CCR4-NOT complex, Phenotype, developmental delay, intellectual disability, Drosophila, deadenylase complex, Female, regulators, Heterozygote, Receptors, CCR4, Biology, Nervous System Malformations, 03 medical and health sciences, Report, genomics, Humans, Gene, Alleles, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic Variation, Protein ubiquitination, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Neurodevelopmental Disorders, SUBUNIT, RNA, CNOT1, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], exome sequencing, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Contains fulltext : 220423.pdf (Publisher’s version ) (Closed access) CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.
Published: 2020

19. Childhood intellectual disability and parents' mental health: integrating social, psychological and genetic influences

Author: Kate Baker, Claire Hughes, F. Lucy Raymond, Elise Ng-Cordell, and Rory T. Devine
Subjects: Parents, Physical disability, media_common.quotation_subject, Population, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Surveys and Questionnaires, Intellectual disability, medicine, Humans, 0501 psychology and cognitive sciences, Family, education, Child, Neighbourhood (mathematics), Socioeconomic status, media_common, Chromosome Aberrations, education.field_of_study, 05 social sciences, medicine.disease, Mental health, Psychiatry and Mental health, Mental Health, Feeling, Risk assessment, Psychology, 030217 neurology & neurosurgery, 050104 developmental & child psychology, Clinical psychology
Abstract: BackgroundIntellectual disability has a complex effect on the well-being of affected individuals and their families. Previous research has identified multiple risk and protective factors for parental mental health, including socioeconomic circumstances and child behaviour.AimsThis study explored whether genetic cause of childhood intellectual disability contributes to parental well-being.MethodChildren from across the UK with intellectual disability due to diverse genetic causes were recruited to the IMAGINE-ID study. Primary carers completed the Development and Well-being Assessment, including a measure of parental distress (Everyday Feeling Questionnaire). Genetic diagnoses were broadly categorised into aneuploidy, chromosomal rearrangements, copy number variants (CNVs) and single nucleotide variants.ResultsCompared with the UK general population, IMAGINE-ID parents (n = 888) reported significantly elevated emotional distress (Cohen's d = 0.546). Within-sample variation was related to recent life events and the perceived impact of children's difficulties. Impact was predicted by child age, physical disability, autistic characteristics and other behavioural difficulties. Genetic diagnosis also predicted impact, indirectly influencing parental well-being. Specifically, CNVs were associated with higher impact, not explained by CNV inheritance, neighbourhood deprivation or family structure.ConclusionsThe mental health of parents caring for a child with intellectual disability is influenced by child and family factors, converging on parental appraisal of impact. We found that genetic aetiologies, broadly categorised, also influence impact and thereby family risks. Recognition of these risk factors could improve access to support for parents, reduce their long-term mental health needs and improve well-being of individuals with intellectual disability.
Published: 2020

20. De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Author: Marwan Shinawi, Jessica Van Ziffle, Carsten G. Bönnemann, Mohamad A. Mikati, Vandana Shashi, Konrad Platzer, Manju A. Kurian, Katy Barwick, Kathleen A. Leppig, Patrick Devine, F. Lucy Raymond, Tomi L. Toler, Johan Lundgren, Koen L.I. van Gassen, Anne Slavotinek, Saskia N. van der Crabben, Wendy K. Chung, Richard H. van Jaarsveld, Matias Wagner, Rikke S. Møller, Marie T. McDonald, Pia Zacher, Kristen Wigby, Heather C Mefford, Dewi P. Bakker, Jennifer Friedman, Angus John Clarke, Joseph T. Shieh, Holly E. Babcock, Julian R. Sampson, Amy McTague, Jamal Ghoumid, Bernt Popp, Saskia B. Wortmann, Emma Hobson, Michaela Bonfert, Gabriella Horvath, Chiara Klöckner, Virgina Lee, Cyril Mignot, Yuri A. Zarate, Jennifer A. Sullivan, Marie-José H. van den Boogaard, Johannes R. Lemke, Alba Sanchis-Juan, Tommy Stödberg, Heinrich Sticht, Eva H. Brilstra, Alyssa Gates, Caroline Nava, Nicholas Stong, Sandra Donkervoort, Alexandrea Wadley, Boris Keren, Jamie L. Fraser, Ashley C. Taylor, Jennifer Keller-Ramey, Human Genetics, Pediatric surgery, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Human genetics
Subjects: medicine.medical_specialty, Movement disorders, Synaptosomal-Associated Protein 25, Bioinformatics, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Atrophy, Intellectual Disability, Intellectual disability, Medicine, STXBP1, Missense mutation, Humans, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Brain Diseases, business.industry, STX1B, medicine.disease, Phenotype, Neurodevelopmental Disorders, Child, Preschool, Medical genetics, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Purpose\ud This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.\ud \ud Methods\ud Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.\ud \ud Results\ud The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.\ud \ud Conclusion\ud We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed “SNAREopathies.”
Published: 2020
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21. Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals with 56 Distinct Heterozygous NFKB1 Mutations

Author: Tiziana Lorenzini, Manfred Fliegauf, Nils Klammer, Natalie Frede, Michele Proietti, Alla Bulashevska, Nadezhda Camacho-Ordonez, Markku Varjosalo, Matias Kinnunen, Esther de Vries, Jos W.M. van der Meer, Rohan Ameratunga, Chaim M. Roifman, Yael D. Schejter, Robin Kobbe, Timo Hautala, Faranaz Atschekzei, Reinhold E. Schmidt, Claudia Schröder, Polina Stepensky, Bella Shadur, Luis A. Pedroza, Michiel van der Flier, Mónica Martínez-Gallo, Luis Ignacio Gonzalez-Granado, Luis M. Allende, Anna Shcherbina, Natalia Kuzmenko, Victoria Zakharova, João Farela Neves, Peter Svec, Ute Fischer, Winnie Ip, Oliver Bartsch, Safa Barış, Christoph Klein, Raif Geha, Janet Chou, Mohammed Alosaimi, Lauren Weintraub, Kaan Boztug, Tatjana Hirschmugl, Maria Marluce Dos Santos Vilela, Dirk Holzinger, Maximilian Seidl, Vassilios Lougaris, Alessandro Plebani, Laia Alsina, Monica Piquer-Gibert, Angela Deyà-Martínez, Charlotte A. Slade, Asghar Aghamohammadi, Hassan Abolhassani, Lennart Hammarström, Outi Kuismin, Merja Helminen, Hana Lango Allen, James E. Thaventhiran, Alexandra F. Freeman, Matthew Cook, Shahrzad Bakhtiar, Mette Christiansen, Charlotte Cunningham-Rundles, Niraj C. Patel, William Rae, Tim Niehues, Nina Brauer, Jaana Syrjänen, Mikko R.J. Seppänen, Siobhan O. Burns, Paul Tuijnenburg, Taco W. Kuijpers, Klaus Warnatz, Bodo Grimbacher, Zoe Adhya, Hana Alachkar, Ariharan Anantharachagan, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William J. Astle, Anthony Attwood, Chiara Bacchelli, Joana Batista, Helen E. Baxendale, Claire Bethune, Shahnaz Bibi, Marta Bleda, Barbara Boardman, Claire Booth, John R. Bradley, Gerome Breen, Matthew Brown, Michael J. Browning, Mary Brownlie, Matthew S. Buckland, Oliver S. Burren, Keren Carss, John Chambers, Anita Chandra, Naomi Clements Brod, Hayley Clifford, Nichola Cooper, Louise C. Daugherty, E.G. Davies, Sophie Davies, John Davis, Sarah Deacock, Sri V.V. Deevi, John Dempster, Lisa A. Devlin, Eleanor F. Dewhurst, Kate Downes, Elizabeth Drewe, Daniel Duarte, J. David M. Edgar, Karen Edwards, William Egner, Tariq El-Shanawany, Marie Erwood, Debra Fletcher, James Fox, Amy J. Frary, Mattia Frontini, Abigail Furnell, H. Bobby Gaspar, Rohit Ghurye, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Pavels Gordins, Stefan Gräf, Luigi Grassi, Daniel Greene, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Matthias Haimel, Lorraine Harper, Grant Hayman, Archana Herwadkar, Fengyuan Hu, Stephen Hughes, Aarnoud P. Huissoon, Roger James, Stephen Jolles, Jennifer Jolley, Julie Jones, Yousuf Karim, Mary A. Kasanicki, Peter Kelleher, Carly Kempster, Sorena Kiani, Nathalie Kingston, Nigel Klein, Myrto Kostadima, Roman Kreuzhuber, Dinakantha Kumararatne, James Laffan, Sara E. Lear, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Paul A. Lyons, Jesmeen Maimaris, Ania Manson, Rutendo Mapeta, Jennifer Martin, Mark I. McCarthy, Elizabeth M. McDermott, Harriet McKinney, Stuart Meacham, Karyn Megy, Hazel Millar, Anoop Mistry, Valerie Morrisson, Sai H.K. Murng, Iman Nasir, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Christopher J. Penkett, Romina Petersen, Mark J. Ponsford, Waseem Qasim, Ellen Quinn, Isabella Quinti, F. Lucy Raymond, Paula J. Rayner-Matthews, Alex Richter, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Sinisa Savic, Suranjith L. Seneviratne, W.A. Carrock Sewell, Denis Seyres, Fiona Shackley, Olga Shamardina, Ilenia Simeoni, Michael A. Simpson, Kenneth G.C. Smith, Simon Staines, Emily Staples, Hannah Stark, Hans Stauss, Cathal L. Steele, Jonathan Stephens, Kathleen E. Stirrups, David Thomas, Moira J. Thomas, Patrick Thomas, Adrian J. Thrasher, Tobias Tilly, Catherine Titterton, Paul Treadaway, Salih Tuna, Ernest Turro, Rafal Urniaz, Julie von Ziegenweidt, Neil Walker, Christopher Watt, Steven B. Welch, Deborah Whitehorn, Lisa Willcocks, Nicholas Wood, Yvette Wood, Sarita Workman, Austen Worth, Katherine Yates, Nigel Yeatman, Patrick F.K. Yong, Timothy Young, Ping Yu, Eliska Zlamalova, Tranzo, Scientific center for care and wellbeing, Huisarts & Ziekenhuis, Lorenzini, Tiziana, Fliegauf, Manfred, Klammer, Nils, Frede, Natalie, Proietti, Michele, Bulashevska, Alla, Camacho-Ordonez, Nadezhda, Varjosalo, Markku, Kinnunen, Matias, de Vries, Esther, van der Meer, Jos W. M., Ameratunga, Rohan, Roifman, Chaim M., Schejter, Yael D., Kobbe, Robin, Hautala, Timo, Atschekzei, Faranaz, Schmidt, Reinhold E., Schroeder, Claudia, Stepensky, Polina, Shadur, Bella, Pedroza, Luis A., van der Flier, Michiel, Martinez-Gallo, Monica, Ignacio Gonzalez-Granado, Luis, Allende, Luis M., Shcherbina, Anna, Kuzmenko, Natalia, Zakharova, Victoria, Neves, Joao Farela, Svec, Peter, Fischer, Ute, Ip, Winnie, Bartsch, Oliver, Baris, Safa, Klein, Christoph, Geha, Raif, Chou, Janet, Alosaimi, Mohammed, Weintraub, Lauren, Boztug, Kaan, Hirschmugl, Tatjana, Dos Santos Vilela, Maria Marluce, Holzinger, Dirk, Seidl, Maximilian, Lougaris, Vassilios, Plebani, Alessandro, Alsina, Laia, Piquer-Gibert, Monica, Deya-Martinez, Angela, Slade, Charlotte A., Aghamohammadi, Asghar, Abolhassani, Hassan, Hammarstrom, Lennart, Kuismin, Outi, Helminen, Merja, Allen, Hana Lango, Thaventhiran, James E., Freeman, Alexandra F., Cook, Matthew, Bakhtiar, Shahrzad, Christiansen, Mette, Cunningham-Rundles, Charlotte, Patel, Niraj C., Rae, William, Niehues, Tim, Brauer, Nina, Syrjanen, Jaana, Seppanen, Mikko R. J., Burns, Siobhan O., Tuijnenburg, Paul, Kuijpers, Taco W., Warnatz, Klaus, Grimbacher, Bodo, Experimental Immunology, Graduate School, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Molecular Systems Biology, Institute of Biotechnology, University of Helsinki, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Children's Hospital, HUS Children and Adolescents, Clinicum, Department of Medicine, and Pediatric surgery
Subjects: 0301 basic medicine, Male, NF-KAPPA-B, Medizin, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Fluorescent Antibody Technique, Autoimmunity, Disease, NUCLEAR-FACTOR, Kaplan-Meier Estimate, medicine.disease_cause, Hypogammaglobulinemia, 0302 clinical medicine, NFKB1 variants and mutations, autosomal dominant inheritance, common variable immunodeficiency, reduced penetrance, variable expressivity, HDE PED, Immunology and Allergy, variants and mutations, NF-κB1-related phenotype, Immunodeficiency, IMMUNODEFICIENCY, NF-?B1-related phenotype, 1184 Genetics, developmental biology, physiology, Disease Management, Middle Aged, NF-kappa B1-related phenotype, Prognosis, Penetrance, Immunohistochemistry, Magnetic Resonance Imaging, 3. Good health, Phenotype, NFKB1 variant, Female, Haploinsufficiency, NFKB1 mutation, Adult, Heterozygote, Immunology, HAPLOINSUFFICIENCY, Article, 03 medical and health sciences, autosomal dominant, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, business.industry, Common variable immunodeficiency, NF-kappa B p50 Subunit, NF-KAPPA-B1, Immune dysregulation, medicine.disease, 030104 developmental biology, Biological Variation, Population, CELLS, Mutation, Primary immunodeficiency, 3111 Biomedicine, business, Tomography, X-Ray Computed, Biomarkers, 030215 immunology
Abstract: Contains fulltext : 229571.pdf (Publisher’s version ) (Closed access) BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
Published: 2020
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22. Structural Analysis of Pathogenic Missense Mutations in GABRA2 and Identification of a Novel de Novo Variant in the Desensitization Gate

Author: Katy Barwick, Alba Sanchis-Juan, F Lucy Raymond, Amy McTague, James A Baker, Manju A Kurian, Keren J. Carss, Nihr BioResource, Marcia Anahí Hasenahuer, Janet M. Thornton, Sofia Duarte, Sanchis-Juan, Alba [0000-0003-2788-5497], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, lcsh:QH426-470, medicine.medical_treatment, Protein domain, Cys-loop receptor, Mutation, Missense, 030105 genetics & heredity, Biology, Molecular Dynamics Simulation, 03 medical and health sciences, Protein Domains, Genetics, medicine, Missense mutation, Humans, GABRA2, Receptor, Child, Molecular Biology, Genetics (clinical), Desensitization (medicine), Whole genome sequencing, Language Disorders, Epilepsy, protein structural analysis, HDE NEU PEd, Original Articles, Receptors, GABA-A, Early Infantile Epileptic Encephalopathy, Cys‐loop receptor, lcsh:Genetics, Transmembrane domain, epileptic encephalopathy, 030104 developmental biology, whole-genome sequencing, biology.protein, Original Article, Female, Protein Multimerization, Stereotyped Behavior, whole‐genome sequencing, Ion Channel Gating
Abstract: Background Cys‐loop receptors control neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six missense variants in GABRA2, a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE). We identified a novel de novo missense variant in GABRA2 in a patient with EIEE and performed protein structural analysis of the seven variants. Methods The novel variant was identified by trio whole‐genome sequencing. We performed protein structural analysis of the seven variants, and compared them to previously reported pathogenic mutations at equivalent positions in other Cys‐loop receptors. Additionally, we studied the distribution of disease‐associated variants in the transmembrane helices of these proteins. Results The seven variants are in the transmembrane domain, either close to the desensitization gate, the activation gate, or in inter‐subunit interfaces. Six of them have pathogenic mutations at equivalent positions in other Cys‐loop receptors, emphasizing the importance of these residues. Also, pathogenic mutations are more common in the pore‐lining helix, consistent with this region being highly constrained for variation in control populations. Conclusion Our study reports a novel pathogenic variant in GABRA2, characterizes the regions where pathogenic mutations are in the transmembrane helices, and underscores the value of considering sequence, evolutionary, and structural information as a strategy for variant interpretation of novel missense mutations., This study reports a novel pathogenic variant in GABRA2, characterizes the regions where pathogenic mutations are in the transmembrane helices, and underscores the value of considering sequence, evolutionary, and structural information as a strategy for variant interpretation of novel missense mutations.
Published: 2020

23. KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation

Author: Nihr BioResource, F. Lucy Raymond, Shekeeb S. Mohammad, TD Graves, Susan J. Hayflick, Bert B.A. de Vries, Katy Barwick, Conor Fearon, Dora Steel, Mark Hallett, Asif Doja, Emilie Chan Seng, Camilo Toro, Fiona Stewart, Diane Demailly, Suh Young Jeong, Claudio M. de Gusmao, Frédérique Pavillard, Nutan Sharma, Fabienne Cyprien, Juan C Pallais, Brent L. Fogel, David R. FitzPatrick, Lucia Abela, Russell C. Dale, Bettina Balint, Natalie Trump, Michel Tchan, Sony Malhotra, Swasti Pal, Maya Topf, Manju A. Kurian, Michelle Sahagian, Julia Rankin, Laila Selim, Jeff L. Waugh, Sidney Krystal, Gustavo Polo, Caleb Rogers, Michel Mondain, Kailash P. Bhatia, Ishwar C. Verma, Marisela Dy-Hollins, Kelly A. Mills, Derek Wong, Laura Cif, William A. Gahl, Meredith W Allain, Sanaz Attaripour Isfahani, Agathe Roubertie, Jenny L. Wilson, Allison Gregory, Victoria Gonzalez, Carolyn D. Applegate, Nathalie Dorison, Jennifer A. Bassetti, Catherine Blanchet, Ada Hamosh, Deciphering Developmental Disorders Study, Hane Lee, Julien Baleine, Emma L. Baple, Gaetan Lesca, Anna Znaczko, Thomas Roujeau, Mario Sa, Laurence Lion François, Neil Mahant, Diane Doummar, Sandra Jansen, Marie Hully, Christine Coubes, Eva B. Forman, Victor S.C. Fung, Gaëtan Poulen, Raghda Zaitoun, Serena Galosi, Timothy Lynch, Xavier Vasques, Elise Schaefer, Richard Selway, Adeline Ngoh, Tuula Rinne, Philippe Coubes, Elizabeth L. Fieg, Rachel Fox, Jennifer Friedman, Andrea K. Petersen, Hugo Morales-Briceño, Rebecca Signer, Luis Rohena, Sandra Chantot Bastaraud, Chloé Laurencin, Kishore R. Kumar, Julian A. Martinez-Agosto, Ellyn Farrelly, Kathleen M. Gorman, Esther Meyer, Joel B. Krier, Ariane Soldatos, Lydie Burglen, Jean-Pierre Lin, Pierre-François Perrigault, Dolly Zhen, Harutomo Hasegawa, Mary D. King, Alba Sanchis-Juan, David A. Stevenson, Gilles Cambonie, Wui K. Chong, Christophe Milési, Vincent d'Hardemare, John R. Østergaard, Laboratoire de Recherche en Neurosciences Cliniques, IBM Systems Group, Service de Neurochirurgie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Gui de Chauliac [Montpellier], Evelina London Children's Hospital, Institute of Child Health [London], University College of London [London] (UCL), Birkbeck College [University of London], Great Ormond Street Hospital for Children [London] (GOSH), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Royal Devon and Exeter NHS Foundation Trust [UK], and Stanford University
Subjects: 0301 basic medicine, Male, Pediatrics, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Deep Brain Stimulation, DYT1 DYSTONIA, GENERALIZED DYSTONIA, VARIANTS, Cohort Studies, 0302 clinical medicine, genetics, [MATH]Mathematics [math], Deep brain stimulation (DBS), Child, Laryngeal dystonia, ComputingMilieux_MISCELLANEOUS, Dystonia, Fetal Growth Retardation, neurodevelopment, Parkinsonism, KMT2B, 3. Good health, INSIGHTS, Phenotype, Treatment Outcome, Dystonic Disorders, Child, Preschool, Cohort, Disease Progression, deep brain stimulation (DBS), dystonia, Female, Chromosome Deletion, Adult, medicine.medical_specialty, Deep brain stimulation, Adolescent, DATABASE, Mutation, Missense, Endocrine System Diseases, Laryngeal Diseases, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, medicine, Genetics, Humans, Computer Simulation, Gait Disorders, Neurologic, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, MUTATIONS, Histone-Lysine N-Methyltransferase, Original Articles, medicine.disease, Status dystonicus, 030104 developmental biology, Disease Presentation, Brain stimulation, Mutation, Quality of Life, Neurology (clinical), business, FOLLOW-UP, GAIT, 030217 neurology & neurosurgery, SYSTEM
Abstract: Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
Published: 2020
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24. Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior

Author: F. Lucy Raymond, Lonneke de Boer, Michal Minczuk, Rami Abou Jamra, Nadja Dinges, Modi Safra, Zubair M. Ahmed, Detilina Grozeva, Hans van Bokhoven, Pedro Rebelo-Guiomar, Mohsin Shahzad, Clara Soyris, Violeta Morin, Mureed Hussain, Nadine Körtel, Michael Stock, Saima Riazuddin, Daniel L. Polla, Jean-Yves Roignant, Arjan P.M. de Brouwer, Avia Zisso, André Reis, Schraga Schwartz, Christopher A. Powell, David A. Koolen, Sheikh Riazuddin, Rolph Pfundt, and Franziska Schwarz
Subjects: Male, 0301 basic medicine, Microcephaly, Adolescent, Poison control, Dwarfism, Biology, Short stature, Gene Knockout Techniques, 03 medical and health sciences, Exon, All institutes and research themes of the Radboud University Medical Center, RNA, Transfer, Intellectual Disability, Report, Intellectual disability, Genetics, medicine, Animals, Humans, Language Development Disorders, RNA, Messenger, Child, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Homozygote, Genetic Variation, RNA, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Exons, medicine.disease, Pedigree, Aggression, Drosophila melanogaster, Phenotype, 030104 developmental biology, Speech delay, Transfer RNA, Female, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs(∗)20), c.1348C>T (p.Arg450(∗)), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.
Published: 2018
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25. ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions

Author: Courtney E. French, Konrad Scheffler, Andrew M. Gross, Giuseppe Narzisi, Bryan R. Lajoie, Joke J.F.A. van Vugt, Sai Chen, Lucy Raymond, David R. Bentley, Roman Petrovski, Peter Krusche, Ryan J. Taft, Alba Sanchis-Juan, Felix Schlesinger, Dorothea Emig-Agius, Egor Dolzhenko, Kristina Ibáñez, Brett Bowman, Jan H. Veldink, Arianna Tucci, Viraj Deshpande, and Michael A. Eberle
Subjects: Statistics and Probability, Source code, Genotype, Computer science, media_common.quotation_subject, Locus (genetics), Computational biology, Variation (game tree), Biochemistry, Sequence graph, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Molecular Biology, Genotyping, 030304 developmental biology, Sequence (medicine), media_common, 0303 health sciences, Genome Analysis, Applications Notes, Computer Science Applications, Computational Mathematics, ComputingMethodologies_PATTERNRECOGNITION, Computational Theory and Mathematics, chemistry, Microsatellite, Software, 030217 neurology & neurosurgery, DNA, Microsatellite Repeats
Abstract: Summary We describe a novel computational method for genotyping repeats using sequence graphs. This method addresses the long-standing need to accurately genotype medically important loci containing repeats adjacent to other variants or imperfect DNA repeats such as polyalanine repeats. Here we introduce a new version of our repeat genotyping software, ExpansionHunter, that uses this method to perform targeted genotyping of a broad class of such loci. Availability and implementation ExpansionHunter is implemented in C++ and is available under the Apache License Version 2.0. The source code, documentation, and Linux/macOS binaries are available at https://github.com/Illumina/ExpansionHunter/. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2019
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26. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018
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27. Identification of genetic variants associated with Huntington's disease progression

Author: Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, Peter Holmans, Lesley Jones, Sarah J Tabrizi, A Coleman, R Dar Santos, J Decolongon, A Sturrock, E Bardinet, C Jauff Ret, D Justo, S Lehericy, C Marelli, K Nigaud, R Valabrègue, SJA van den Bogaard, E M Dumas, J van der Grond, EP t'Hart, C Jurgens, M-N Witjes-Ane, N Arran, J Callaghan, C Stopford, C Frost, R Jones, N Hobbs, N Lahiri, R Ordidge, G Owen, T Pepple, J Read, M Say, E Wild, A Patel, N C Fox, C Gibbard, I Malone, H Crawford, D Whitehead, S Keenan, D M Cash, C Berna, N Bechtel, S Bohlen, A Hoff Man, P Kraus, E Axelson, C Wang, T Acharya, S Lee, W Monaco, C Campbell, S Queller, K Whitlock, M Campbell, E Frajman, C Milchman, A O'Regan, I Labuschagne, J Stout, B Landwehrmeyer, D Craufurd, R Scahill, S Hicks, C Kennard, H Johnson, A Tobin, HD Rosas, R Reilmann, B Borowsky, C Pourchot, S C Andrews, Anne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael Bonelli, Jean-Marc Burgunder, Stephen Dunnett, Joaquim Ferreira, Olivia Handley, Arvid Heiberg, Torsten Illmann, G. Bernhard Landwehrmeyer, Jamie Levey, Maria A. Ramos-Arroyo, Jørgen Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A.C. Roos, A Rojo Sebastián, Sarah Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Monica Bascuñana Garde, Sabrina Betz, Reineke Bos, Jenny Callaghan, Adrien Come, Leonor Correia Guedes, Daniel Ecker, Ana Maria Finisterra, Ruth Fullam, Mette Gilling, Lena Gustafsson, Olivia J Handley, Carina Hvalstedt, Christine Held, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saül Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Michael Orth, Hélène Padieu, Laurent Paterski, Nadia Peppa, Martina Di Renzo, Amandine Rialland, Niini Røren, Pavla Šašinková, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Wildson Vieira da Silva, Marleen R van Walsem, Carina Whalstedt, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Raphael M. Bonelli, Sabine Lilek, Karen Hecht, Brigitte Herranhof, Anna Holl, Hans-Peter Kapfhammer, Michael Koppitz, Markus Magnet, Nicole Müller, Daniela Otti, Annamaria Painold, Karin Reisinger, Monika Scheibl, Helmut Schöggl, Jasmin Ullah, Eva-Maria Braunwarth, Florian Brugger, Lisa Buratti, Eva-Maria Hametner, Caroline Hepperger, Christiane Holas, Anna Hotter, Anna Hussl, Christoph Müller, Werner Poewe, Klaus Seppi, Fabienne Sprenger, Gregor Wenning, Andrea Boogaerts, Godelinde Calmeyn, Isabelle Delvaux, Dirk Liessens, Nele Somers, Michel Dupuit, Cécile Minet, Dominique van Paemel, Pascale Ribaï, Dimphna van Reijen, Jirí Klempír, Veronika Majerová, Jan Roth, Irena Stárková, Lena E. Hjermind, Oda Jacobsen, Jørgen E. Nielsen, Ida Unmack Larsen, Tua Vinther-Jensen, Heli Hiivola, Hannele Hyppönen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau, Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Rekha Barthélémy, Christelle De Bruycker, Maryline Cabaret Anne-Sophie Carette, Eric Decorte Luc Defebvre, Marie Delliaux, Arnaud Delval, Alain Destee, Kathy Dujardin, Marie-Hélène Lemaire, Sylvie Manouvrier, Mireille Peter, Lucie Plomhouse, Bernard Sablonnière, Clémence Simonin, Stéphanie Thibault-Tanchou, Isabelle Vuillaume, Marcellin Bellonet, Hassan Berrissoul, Stéphanie Blin, Françoise Courtin, Cécile Duru, Véronique Fasquel, Olivier Godefroy, Pierre Krystkowiak, Béatrice Mantaux, Martine Roussel, Sandrine Wannepain, Jean-Philippe Azulay, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Laura Mundler, Mathieu Anheim, Celine Julié, Ouhaid Lagha Boukbiza, Nadine Longato, Gabrielle Rudolf, Christine Tranchant, Marie-Agathe Zimmermann, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J. Werner, Harald Gelderblom, Josef Priller, Harald Prüß, Eike Jakob Spruth, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Peter Kotz, Christian Prehn, Carsten Saft, Herwig Lange, Robert Maiwald, Matthias Löhle, Antonia Maass, Simone Schmidt, Cecile Bosredon, Alexander Storch, Annett Wolz, Martin Wolz, Philipp Capetian, Johann Lambeck, Birgit Zucker, Kai Boelmans, Christos Ganos, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Heike Gorzolla, Christoph Schrader, Pawel Tacik, Michael Ribbat, Bernhard Longinus, Katrin Bürk, Jens Carsten Möller, Ida Rissling, Mark Mühlau, Alexander Peinemann, Michael Städtler, Adolf Weindl, Juliane Winkelmann, Cornelia Ziegler, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Eva Hölzner, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Natalia Weber, Matthias Dose, Gabriele Leythäuser, Ralf Marquard, Tina Raab, Alexandra Wiedemann, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Christina Lang, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süßmuth, Sonja Trautmann, Patrick Weydt, Claudia Cormio, Vittorio Sciruicchio, Claudia Serpino, Marina de Tommaso, Sabina Capellari, Pietro Cortelli, Roberto Galassi, Giovanni Rizzo, Roberto Poda, Cesa Scaglione, Elisabetta Bertini, Elena Ghelli, Andrea Ginestroni, Francesca Massaro, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giovanni Abbruzzese, Monica Bandettini di Poggio, Giovanna Ferrandes, Paola Mandich, Roberta Marchese, Alberto Albanese, Daniela Di Bella, Anna Castaldo, Stefano Di Donato, Cinzia Gellera, Silvia Genitrini, Caterina Mariotti, Lorenzo Nanetti, Dominga Paridi, Paola Soliveri, Chiara Tomasello, Giuseppe De Michele, Luigi Di Maio, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Elena Salvatore, Pierpaolo Sorrentino, Enrico Amico, Mariagrazia Favellato, Annamaria Griguoli, Irene Mazzante, Martina Petrollini, Ferdinando Squitieri, Barbara D'Alessio, Chiara Esposito, Rita Bentivoglio, Marina Frontali, Arianna Guidubaldi, Tamara Ialongo, Gioia Jacopini, Carla Piano, Silvia Romano, Francesco Soleti, Maria Spadaro, Monique S.E. van Hout, Marloes E. 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Bosca, Francisco Castera Brugada, Juan Andres Burguera, Anabel Campos, Garcia Carmen Peiró Vilaplana, Peter Berglund, Radu Constantinescu, Gunnel Fredlund, Ulrika Høsterey-Ugander, Petra Linnsand, Liselotte Neleborn-Lingefjärd, Magnus Wentzel, Ghada Loutfi, Carina Olofsson, Eva-Lena Stattin, Laila Westman, Birgitta Wikström, Yanik Stebler, Alain Kaelin, Irene Romero, Michael Schüpbach, Sabine Weber Zaugg, Maria Hauer, Roman Gonzenbach, Hans H. Jung, Violeta Mihaylova, Jens Petersen, Roisin Jack, Kirsty Matheson, Zosia Miedzybrodzka, Daniela Rae, Sheila A Simpson, Fiona Summers, Alexandra Ure, Vivien Vaughan, Shahbana Akhtar, Jenny Crooks, Adrienne Curtis, Jenny de Souza, John Piedad, Hugh Rickards, Jan Wright, Elizabeth Coulthard, Louise Gethin, Beverley Hayward, Kasia Sieradzan, Matthew Armstrong, Roger A. Barker, Deidre O'Keefe, Anna Di Pietro, Kate Fisher, Anna Goodman, Susan Hill, Ann Kershaw, Sarah Mason, Nicole Paterson, Lucy Raymond, Rachel Swain, Natalie Valle Guzman, Monica Busse, Cynthia Butcher, Catherine Clenaghan, Sarah Hunt, Una Jones, Hanan Khalil, Michael Owen, Kathleen Price, Anne Rosser, Maureen Edwards, Carrie Ho, Teresa Hughes, Marie McGill, Pauline Pearson, Mary Porteous, Paul Smith, Peter Brockie, Jillian Foster, Nicola Johns, Sue McKenzie, Jean Rothery, Gareth Thomas, Shona Yates, Liz Burrows, Carol Chu, Amy Fletcher, Deena Gallantrae, Stephanie Hamer, Alison Harding, Stefan Klöppel, Alison Kraus, Fiona Laver, Monica Lewis, Mandy Longthorpe, Ivana Markova, Ashok Raman, Nicola Robertson, Mark Silva, Aileen Thomson, Sue Wild, Pam Yardumian, Carole Evans, Deena Gallentrae, Emma Hobson, Stuart Jamieson, Hannah Musgrave, Liz Rowett, Jean Toscano, Colin Bourne, Jackie Clapton, Carole Clayton, Heather Dipple, Dawn Freire-Patino, Janet Grant, Diana Gross, Caroline Hallam, Julia Middleton, Ann Murch, Catherine Thompson, Sundus Alusi, Rhys Davies, Kevin Foy, Emily Gerrans, Louise Pate, Thomasin Andrews, Andrew Dougherty, Charlotte Golding, Fred Kavalier, Hana Laing, Alison Lashwood, Dene Robertson, Deborah Ruddy, Alastair Santhouse, Anna Whaite, Stefania Bruno, Karen Doherty, Salman Haider, Davina Hensman, Nayana Lahiri, Marianne Novak, Aakta Patel, Elisabeth Rosser, Rachel Taylor, Thomas Warner, Edward Wild, Natalie Arran, Judith Bek, David Craufurd, Marianne Hare, Liz Howard, Susan Huson, Liz Johnson, Mary Jones, Helen Murphy, Emma Oughton, Lucy Partington-Jones, Dawn Rogers, Andrea Sollom, Julie Snowden, Cheryl Stopford, Jennifer Thompson, Iris Trender-Gerhard, Nichola Verstraelen, Leann Westmoreland, Richard Armstrong, Kathryn Dixon, Andrea H Nemeth, Gill Siuda, Ruth Valentine, David Harrison, Max Hughes, Andrew Parkinson, Beverley Soltysiak, Oliver Bandmann, Alyson Bradbury, Paul Gill, Helen Fairtlough, Kay Fillingham, Isabella Foustanos, Mbombe Kazoka, Kirsty O'Donovan, Cat Taylor, Katherine Tidswell, Oliver Quarrell, Puay Ngoh Lau, Emmanul Pica, Louis Tan, Univ Angers, Okina, Moss, Davina J. Hensman, Tabrizi, Sarah J, Mead, Simon, Kitty, Lo, Pardiã±as, Antonio F, Holmans, Peter, Jones, Lesley, Langbehn, Dougla, Coleman, A., Santos, R. Dar, Decolongon, J., Sturrock, A., Bardinet, E., Ret, C. Jauff, Justo, D., Lehericy, S., Marelli, C., Nigaud, K., Valabrãgue, R., van den Bogaard, S. J. A., Dumas, E. M., van der Grond, J., T'Hart, E. P., Jurgens, C., Witjes-Ane, M. -. N., Arran, N., Callaghan, J., Stopford, C., Frost, C., Jones, R., Hobbs, N., Lahiri, N., Ordidge, R., Owen, G., Pepple, T., Read, J., Say, M., Wild, E., Patel, A., Fox, N. C., Gibbard, C., Malone, I., Crawford, H., Whitehead, D., Keenan, S., Cash, D. M., Berna, C., Bechtel, N., Bohlen, S., Man, A. Hoff, Kraus, P., Axelson, E., Wang, C., Acharya, T., Lee, S., Monaco, W., Campbell, C., Queller, S., Whitlock, K., Campbell, M., Frajman, E., Milchman, C., O'Regan, A., Labuschagne, I., Stout, J., Landwehrmeyer, B., Craufurd, D., Scahill, R., Hicks, S., Kennard, C., Johnson, H., Tobin, A., Rosas, H. D., Reilmann, R., Borowsky, B., Pourchot, C., Andrews, S. C., Bachoud-LÃ©vi, Anne-Catherine, Bentivoglio, Anna Rita, Biunno, Ida, Bonelli, Raphael, Burgunder, Jean-Marc, Dunnett, Stephen, Ferreira, Joaquim, Handley, Olivia, Heiberg, Arvid, Illmann, Torsten, Landwehrmeyer, G. Bernhard, Levey, Jamie, Ramos-Arroyo, Maria A., Nielsen, Jã¸rgen, Koivisto, Susana Pro, Pã¤ivã¤rinta, Markku, Roos, Raymund A. C., Sebastiã¡n, A. Rojo, Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlstrã¶m, Jan, Zaremba, Jacek, Baake, Verena, Barth, Katrin, Garde, Monica BascuÃ±ana, Betz, Sabrina, Bos, Reineke, Callaghan, Jenny, Come, Adrien, Guedes, Leonor Correia, Ecker, Daniel, Finisterra, Ana Maria, Fullam, Ruth, Gilling, Mette, Gustafsson, Lena, Handley, Olivia J, Hvalstedt, Carina, Held, Christine, Koppers, Kerstin, Lamanna, Claudia, Laurã , Matilde, Descals, AsunciÃ³n MartÃnez, Martinez-Horta, Saã¼l, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mã¼tze, Lisanne, Oehmen, Martin, Orth, Michael, Padieu, Hã©lãne, Paterski, Laurent, Peppa, Nadia, Di Renzo, Martina, Rialland, Amandine, Rã¸ren, Niini, Å aå¡inkovã¡, Pavla, Timewell, Erika, Townhill, Jenny, Cubillo, Patricia Trigo, da Silva, Wildson Vieira, van Walsem, Marleen R, Whalstedt, Carina, Witjes-AnÃ©, Marie-Noelle, Witkowski, Grzegorz, Wright, Abigail, Zielonka, Daniel, Zielonka, Eugeniusz, Zinzi, Paola, Bonelli, Raphael M., Lilek, Sabine, Hecht, Karen, Herranhof, Brigitte, Holl, Anna, Kapfhammer, Hans-Peter, Koppitz, Michael, Magnet, Marku, Mã¼ller, Nicole, Otti, Daniela, Painold, Annamaria, Reisinger, Karin, Scheibl, Monika, Schã¶ggl, Helmut, Ullah, Jasmin, Braunwarth, Eva-Maria, Brugger, Florian, Buratti, Lisa, Hametner, Eva-Maria, Hepperger, Caroline, Holas, Christiane, Hotter, Anna, Hussl, Anna, Mã¼ller, Christoph, Poewe, Werner, Seppi, Klau, Sprenger, Fabienne, Wenning, Gregor, Boogaerts, Andrea, Calmeyn, Godelinde, Delvaux, Isabelle, Liessens, Dirk, Somers, Nele, Dupuit, Michel, Minet, Cã©cile, van Paemel, Dominique, Ribaã¯, Pascale, van Reijen, Dimphna, Klempãr, Jirã, Majerovã¡, Veronika, Roth, Jan, Stã¡rkovã¡, Irena, Hjermind, Lena E., Jacobsen, Oda, Nielsen, JÃ¸rgen E., Larsen, Ida Unmack, Vinther-Jensen, Tua, Hiivola, Heli, Hyppã¶nen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau, Dominique, Bost, Marie, Gohier, Bã©nã©dicte, Guã©rid, Marie-Anne, Olivier, Audrey, Prundean, Adriana, Scherer-Gagou, Clarisse, Verny, Christophe, Babiloni, Blandine, Debruxelles, Sabrina, Duchã©, Charlotte, Goizet, Cyril, Jameau, Laetitia, Lafoucriãre, Danielle, Spampinato, Umberto, Barthã©lã©my, Rekha, De Bruycker, Christelle, Carette, Maryline Cabaret Anne-Sophie, Defebvre, Eric Decorte Luc, Delliaux, Marie, Delval, Arnaud, Destee, Alain, Dujardin, Kathy, Lemaire, Marie-HÃ©lÃne, Manouvrier, Sylvie, Peter, Mireille, Plomhouse, Lucie, Sablonniãre, Bernard, Simonin, Clã©mence, Thibault-Tanchou, Stã©phanie, Vuillaume, Isabelle, Bellonet, Marcellin, Berrissoul, Hassan, Blin, Stã©phanie, Courtin, Franã§oise, Duru, Cã©cile, Fasquel, Vã©ronique, Godefroy, Olivier, Krystkowiak, Pierre, Mantaux, Bã©atrice, Roussel, Martine, Wannepain, Sandrine, Azulay, Jean-Philippe, Delfini, Marie, Eusebio, Alexandre, Fluchere, Frã©dã©rique, Mundler, Laura, Anheim, Mathieu, Juliã©, Celine, Boukbiza, Ouhaid Lagha, Longato, Nadine, Rudolf, Gabrielle, Tranchant, Christine, Zimmermann, Marie-Agathe, Kosinski, Christoph Michael, Milkereit, Eva, Probst, Daniela, Reetz, Kathrin, Sass, Christian, Schiefer, Johanne, Schlangen, Christiane, Werner, Cornelius J., Gelderblom, Harald, Priller, Josef, Prã¼ã , Harald, Spruth, Eike Jakob, Ellrichmann, Gisa, Herrmann, Lennard, Hoffmann, Rainer, Kaminski, Barbara, Kotz, Peter, Prehn, Christian, Saft, Carsten, Lange, Herwig, Maiwald, Robert, Lã¶hle, Matthia, Maass, Antonia, Schmidt, Simone, Bosredon, Cecile, Storch, Alexander, Wolz, Annett, Wolz, Martin, Capetian, Philipp, Lambeck, Johann, Zucker, Birgit, Boelmans, Kai, Ganos, Christo, Heinicke, Walburgi, Hidding, Ute, Lewerenz, Jan, Mã¼nchau, Alexander, Schmalfeld, Jenny, Stubbe, Lar, Zittel, Simone, Diercks, Gabriele, Dressler, Dirk, Gorzolla, Heike, Schrader, Christoph, Tacik, Pawel, Ribbat, Michael, Longinus, Bernhard, Bã¼rk, Katrin, Mã¶ller, Jens Carsten, Rissling, Ida, Mã¼hlau, Mark, Peinemann, Alexander, Stã¤dtler, Michael, Weindl, Adolf, Winkelmann, Juliane, Ziegler, Cornelia, Bechtel, Natalie, Beckmann, Heike, Bohlen, Stefan, Hã¶lzner, Eva, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Natalia, Dose, Matthia, Leythã¤user, Gabriele, Marquard, Ralf, Raab, Tina, Wiedemann, Alexandra, Buck, Andrea, Connemann, Julia, Geitner, Carolin, Kesse, Andrea, Landwehrmeyer, Bernhard, Lang, Christina, Lezius, Franziska, Nepper, Solveig, Niess, Anke, Schneider, Ariane, Schwenk, Daniela, Sã¼ã muth, Sigurd, Trautmann, Sonja, Weydt, Patrick, Cormio, Claudia, Sciruicchio, Vittorio, Serpino, Claudia, de Tommaso, Marina, Capellari, Sabina, Cortelli, Pietro, Galassi, Roberto, Rizzo, Giovanni, Poda, Roberto, Scaglione, Cesa, Bertini, Elisabetta, Ghelli, Elena, Ginestroni, Andrea, Massaro, Francesca, Mechi, Claudia, Paganini, Marco, Piacentini, Silvia, Pradella, Silvia, Romoli, Anna Maria, Sorbi, Sandro, Abbruzzese, Giovanni, di Poggio, Monica Bandettini, Ferrandes, Giovanna, Mandich, Paola, Roberta, Marchese, Albanese, Alberto, Di Bella, Daniela, Castaldo, Anna, Di Donato, Stefano, Gellera, Cinzia, Genitrini, Silvia, Mariotti, Caterina, Nanetti, Lorenzo, Paridi, Dominga, Soliveri, Paola, Tomasello, Chiara, De Michele, Giuseppe, Di Maio, Luigi, Massarelli, Marco, Peluso, Silvio, Roca, Alessandro, Russo, Cinzia Valeria, Salvatore, Elena, Sorrentino, Pierpaolo, Amico, Enrico, Favellato, Mariagrazia, Griguoli, Annamaria, Mazzante, Irene, Petrollini, Martina, Squitieri, Ferdinando, D'Alessio, Barbara, Esposito, Chiara, Bentivoglio, Rita, Frontali, Marina, Guidubaldi, Arianna, Ialongo, Tamara, Jacopini, Gioia, Piano, Carla, Romano, Silvia, Soleti, Francesco, Spadaro, Maria, van Hout, Monique S. E., Verhoeven, Marloes E., van Vugt, Jeroen P. P., de Weert, A. Marit, Bolwijn, J. J. W., Dekker, M., Kremer, B., Leenders, K. L., van Oostrom, J. C. H., van den Bogaard, Simon J. A., Dumas, Eve M., â t Hart, Ellen P., Kremer, Berry, Verstappen, C. C. P., Aaserud, Olaf, Jan Frich, C., Wehus, Ragnhild, Bjã¸rgo, Kathrine, Fannemel, Madeleine, Gã¸rvell, Per F., Lorentzen, Eirin, Retterstã¸l, Lar, Stokke, Bodil, Bjã¸rnevoll, Inga, Sando, Sigrid Botne, Dziadkiewicz, Artur, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Blaszcyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasinska-Myga, Barbara, Klodowska-Duda, Gabriela, Opala, Gregorz, Stompel, Daniel, Banaszkiewicz, Krzysztof, Bocwinska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Malgorzata, Krawczyk, Malgorzata, Rudzinska, Monika, Szczygiel, Elzbieta, Szczudlik, Andrzej, Wasielewska, Anna, Wã³jcik, Magdalena, Bryl, Anna, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempolowicz, Justyna, Gogol, Anna, Janik, Piotr, Kwiecinski, Hubert, Jamrozik, Zygmunt, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Richter, Przemyslaw, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stepniak, Iwona, Sulek, Anna, Zdzienicka, Elzbieta, Zieora-Jakutowicz, Karolina, Ferreira, Joaquim J, Coelho, Miguel, Mendes, Tiago, Valadas, Anabela, Andrade, Carlo, Gago, Miguel, Garrett, Carolina, Guerra, Maria RosÃ¡lia, Herrera, Carmen DurÃ¡n, Garcia, Patrocinio Moreno, Barbera, Miquel Aguilar, Guia, Dolors Badene, Hernanz, Laura Casa, Catena, Judit LÃ³pez, Ferrer, Pilar QuilÃ©z, Sebastiã¡n, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Nãºria, Calopa, Matilde, Robert, Misericordia Floriach, Viladrich, Celia Mareca, Idiago, JesÃºs Miguel Ruiz, Riballo, Antonio Villa, Cubo, Esther, Polo, Cecilia Gil, Mariscal, Natividad, Rivadeneyra, Perez Jessica, Barrero, Francisco, Morales, Bla, Fenollar, Marãa, Garcãa, RocÃo GarcÃa-Ramo, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuã±ana, Mã³nica, Caldentey, Juan Garcia, Ventura, Marta FatÃ¡, Ribas, Guillermo GarcÃa, de YÃ©benes, Justo GarcÃa, Moreno, JosÃ© Luis LÃ³pez-SendÃ³n, Frech, Fernando Alonso, Ruãz, Pedro J. GarcÃa, MartÃnez-Descals, Asunciã³n, Guerrero, Rosa, Artiga, MarÃa JosÃ© Saiz, Sã¡nchez, Vicenta, Perea, MarÃa Fuensanta Noguera, Fortuna, Lorenza, Manzanares, Salvadora, Reinante, Gema, Torres, MarÃa Martirio Antequera, Moreau, Laura Vivanco, GonzÃ¡lez GonzÃ¡lez, Sonia, Guisasola, Luis MenÃ©ndez, Salvador, Carlo, Martãn, Esther SuarÃ©z San, Ramirez, InÃ©s Legarda, Gorospe, Aranzazãº, Lopera, MÃ³nica Rodriguez, Arques, Penelope Nava, Rodrãguez, MarÃa JosÃ© Torre, Pastor, Barbara Vive, Gaston, Itziar, Martinez-Jaurrieta, Maria Dolore, Moreno, Jose Manuel Garcia, Lucena, Carolina Mendez, Damas, Fatima, Cortegana, Hermoso Eva Pacheco, Peã±a, JosÃ© ChacÃ³n, Redondo, Lui, Carrillo, Fã¡tima, Teresa CÃ¡ceres, Marãa, Mir, Pablo, Suarez, MarÃa JosÃ© Lama, Vargas-GonzÃ¡lez, Laura, Bosca, Maria E., Brugada, Francisco Castera, Burguera, Juan Andre, Campos, Anabel, Vilaplana, Garcia Carmen PeirÃ³, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, HÃ¸sterey-Ugander, Ulrika, Linnsand, Petra, Neleborn-LingefjÃ¤rd, Liselotte, Wentzel, Magnu, Loutfi, Ghada, Olofsson, Carina, Stattin, Eva-Lena, Westman, Laila, Wikstrã¶m, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schã¼pbach, Michael, Weber Zaugg, Sabine, Hauer, Maria, Gonzenbach, Roman, Jung, Hans H., Mihaylova, Violeta, Petersen, Jen, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, Simpson, Sheila A, Summers, Fiona, Ure, Alexandra, Vaughan, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Armstrong, Matthew, Barker, Roger A., O'Keefe, Deidre, Di Pietro, Anna, Fisher, Kate, Goodman, Anna, Hill, Susan, Kershaw, Ann, Mason, Sarah, Paterson, Nicole, Raymond, Lucy, Swain, Rachel, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Clenaghan, Catherine, Hunt, Sarah, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Edwards, Maureen, Carrie, Ho, Hughes, Teresa, Mcgill, Marie, Pearson, Pauline, Porteous, Mary, Smith, Paul, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Burrows, Liz, Chu, Carol, Fletcher, Amy, Gallantrae, Deena, Hamer, Stephanie, Harding, Alison, Klã¶ppel, Stefan, Kraus, Alison, Laver, Fiona, Lewis, Monica, Longthorpe, Mandy, Markova, Ivana, Raman, Ashok, Robertson, Nicola, Silva, Mark, Thomson, Aileen, Wild, Sue, Yardumian, Pam, Evans, Carole, Gallentrae, Deena, Hobson, Emma, Jamieson, Stuart, Musgrave, Hannah, Rowett, Liz, Toscano, Jean, Bourne, Colin, Clapton, Jackie, Clayton, Carole, Dipple, Heather, Freire-Patino, Dawn, Grant, Janet, Gross, Diana, Hallam, Caroline, Middleton, Julia, Murch, Ann, Thompson, Catherine, Alusi, Sundu, Davies, Rhy, Foy, Kevin, Gerrans, Emily, Pate, Louise, Andrews, Thomasin, Dougherty, Andrew, Golding, Charlotte, Kavalier, Fred, Laing, Hana, Lashwood, Alison, Robertson, Dene, Ruddy, Deborah, Santhouse, Alastair, Whaite, Anna, Bruno, Stefania, Doherty, Karen, Haider, Salman, Hensman, Davina, Lahiri, Nayana, Novak, Marianne, Patel, Aakta, Rosser, Elisabeth, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Rogers, Dawn, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Armstrong, Richard, Dixon, Kathryn, Nemeth, Andrea H, Siuda, Gill, Valentine, Ruth, David, Harrison, Hughes, Max, Parkinson, Andrew, Soltysiak, Beverley, Bandmann, Oliver, Bradbury, Alyson, Gill, Paul, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Kazoka, Mbombe, O'Donovan, Kirsty, Taylor, Cat, Tidswell, Katherine, Quarrell, Oliver, Lau, Puay Ngoh, Pica, Emmanul, Tan, Louis, Amsterdam Neuroscience - Neurodegeneration, Neurology, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Moss, Davina J Hensman, Lo, Kitty, Pardiñas, Antonio F, Santos, R Dar, Ret, C Jauff, Valabrègue, R., Witjes-Ane, M. -N., Man, A Hoff, Bachoud-Lévi, Anne-Catherine, Nielsen, Jørgen, Päivärinta, Markku, Sebastián, A Rojo, Wahlström, Jan, Garde, Monica Bascuñana, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mütze, Lisanne, Padieu, Hélène, Røren, Niini, Šašinková, Pavla, Witjes-Ané, Marie-Noelle, Müller, Nicole, Schöggl, Helmut, Müller, Christoph, Minet, Cécile, Ribaï, Pascale, Klempír, Jirí, Majerová, Veronika, Stárková, Irena, Nielsen, Jørgen E., Hyppönen, Hannele, Gohier, Bénédicte, Guérid, Marie-Anne, Duché, Charlotte, Lafoucrière, Danielle, Barthélémy, Rekha, Lemaire, Marie-Hélène, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Mantaux, Béatrice, Fluchere, Frédérique, Julié, Celine, Prüß, Harald, Löhle, Matthia, Münchau, Alexander, Bürk, Katrin, Möller, Jens Carsten, Mühlau, Mark, Städtler, Michael, Hölzner, Eva, Leythäuser, Gabriele, Süßmuth, Sigurd, Marchese, Roberta, DI MAIO, Luigi, ’t Hart, Ellen P., Bjørgo, Kathrine, Gørvell, Per F., Retterstøl, Lar, Bjørnevoll, Inga, Wójcik, Magdalena, Guerra, Maria Rosália, Herrera, Carmen Durán, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastián, Ana Rojo, Busquets, Núria, Idiago, Jesús Miguel Ruiz, Fenollar, María, García, Rocío García-Ramo, Bascuñana, Mónica, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Ruíz, Pedro J García, Martínez-Descals, Asunción, Artiga, María José Saiz, Sánchez, Vicenta, Perea, María Fuensanta Noguera, Torres, María Martirio Antequera, González González, Sonia, Guisasola, Luis Menéndez, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Rodríguez, María José Torre, Peña, José Chacón, Carrillo, Fátima, Teresa Cáceres, María, Suarez, María José Lama, Vargas-González, Laura, Vilaplana, Garcia Carmen Peiró, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Wikström, Birgitta, Schüpbach, Michael, Ho, Carrie, Klöppel, Stefan, Harrison, David, Cardiff University, University of Iowa [Iowa City], University of British Columbia (UBC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UCL, Institute of Neurology [London], National Oceanography Centre [Southampton] (NOC), University of Southampton, Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), TRACK-HD investigators, Pardinas, Antonio F, Langbehn, Douglas, Lee, S Hong, TRACK-HD Investigators, and REGISTRY Investigators
Subjects: 0301 basic medicine, Oncology, Registrie, Genome-wide association study, Longitudinal Studie, Disease, Bioinformatics, Severity of Illness Index, Principal Component Analysi, Longitudinal Studies, Registries, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Huntington disease, DNA-Binding Proteins, Settore MED/26 - NEUROLOGIA, Adult, Genome-Wide Association Study, Humans, Huntington Disease, MutS Homolog 3 Protein, Principal Component Analysis, Disease Progression, Neurology (clinical), huntingtin gene, age of onest, Huntington’s disease, Human, medicine.medical_specialty, cag repeat, instability, DNA-Binding Protein, Clinical Neurology, Principal component analysis, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Huntington's disease, Internal medicine, medicine, SNP, genome-wide association study, medicine.disease, R1, meta-analysis, Minor allele frequency, 030104 developmental biology, Age of onset, Trinucleotide repeat expansion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.
Published: 2017
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28. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author: Gavin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, Vincent Plagnol, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster, Graeme Black, Georgina Hall, Stuart Ingram, Rachel Gillespie, Forbes Manson, Panagiotis Sergouniotis, Chris Inglehearn, Carmel Toomes, Manir Ali, Martin McKibbin, James Poulter, Kamron Khan, Emma Lord, Andrea Nemeth, Susan Downes, Stephanie Halford, Jing Yu, Stefano Lise, Nikos Ponitkos, Michel Michaelides, Veronica van Heyningen, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), and Med Microbiol, Infect Dis & Infect Prev
Subjects: Male, 0301 basic medicine, Retinal degeneration, Biallelic Mutation, RHOA, PROTEIN, Eye, Medical and Health Sciences, ACTIVATION, chemistry.chemical_compound, 0302 clinical medicine, 2.1 Biological and endogenous factors, Missense mutation, Exome, Aetiology, Genetics (clinical), Genetics & Heredity, Genetics, biology, Retinal Degeneration, Cell Polarity, MOSAIC EYES, Biological Sciences, Middle Aged, Phenotype, inherited retinal dystrophy, Pedigree, UK Inherited Retinal Disease Consortium, Female, apicobasal polarity, Retinal Dystrophies, Adult, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, Genotype, Mutation, Missense, Nerve Tissue Proteins, Retina, 03 medical and health sciences, Rare Diseases, retinitis pigmentosa, Report, CRB1, Retinitis pigmentosa, medicine, Humans, Amino Acid Sequence, Eye Proteins, Eye Disease and Disorders of Vision, Alleles, Human Genome, Neurosciences, Genetic Variation, Membrane Proteins, Epithelial Cells, Retinal, CELL FEATURES, medicine.disease, NUCLEOTIDE EXCHANGE FACTOR, p114RhoGEF, 030104 developmental biology, INTEGRATIVE GENOMICS VIEWER, OKO-MEDUZY, chemistry, Mutation, MORPHOGENESIS, 030221 ophthalmology & optometry, biology.protein, Missense, rhoA GTP-Binding Protein, Rho Guanine Nucleotide Exchange Factors, Genome-Wide Association Study
Abstract: Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.
Published: 2017
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29. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Author: Keren J. Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H. Scott, Emma Clement, Louise Allen, Ruth Armstrong, Angela F. Brady, Jenny Carmichael, Manali Chitre, Robert H.H. Henderson, Jane Hurst, Robert E. MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A. Thompson, Emma Wakeling, Willem H. Ouwehand, Michel Michaelides, Anthony T. Moore, Andrew R. Webster, F. Lucy Raymond, Timothy Aitman, Hana Alachkar, Sonia Ali, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Colin Church, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Rue-Albrecht, K, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Biochemie, Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, Vascular Medicine, and Paediatric Infectious Diseases / Rheumatology / Immunology
Subjects: 0301 basic medicine, Male, DNA Mutational Analysis, EXOME, PROTEIN, Eye, whole-genome sequence, NIHR-BioResource Rare Diseases Consortium, Medical and Health Sciences, Choroideremia, ACTIVATION, 0302 clinical medicine, Ethnicity, 2.1 Biological and endogenous factors, Exome, rare sequence variant, Copy-number variation, Aetiology, MUTATION, Genetics (clinical), Exome sequencing, Genetics & Heredity, Genetics, Genome, Adaptor Proteins, Biological Sciences, DYSTROPHY, copy-number variants, Female, Human, Common disease-common variant, LEBER CONGENITAL AMAUROSIS, Ethnic Groups, Genes, Recessive, Biology, DIAGNOSIS, Article, 03 medical and health sciences, Rare Diseases, Retinal Diseases, STARGARDT DISEASE, Clinical Research, REVEALS, Journal Article, medicine, Recessive, Humans, retinal dystrophy, Eye Disease and Disorders of Vision, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, Base Sequence, Genome, Human, Human Genome, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, GENE, Introns, Stargardt disease, Good Health and Well Being, 030104 developmental biology, Genes, Mutation, 030221 ophthalmology & optometry, Human genome
Abstract: Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
Published: 2017
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30. Creating genetic reports that are understood by nonspecialists: a case study

Author: Lucy Raymond, Chiappi A, Gabriel Recchia, Freeman Alj, Gemma Chandratillake, Recchia, Gabriel [0000-0002-0210-8635], Chiappi, Antonia [0000-0002-9652-8787], Chandratillake, Gemma [0000-0001-5917-7642], Freeman, Alexandra L. J. [0000-0002-4115-161X], Apollo - University of Cambridge Repository, and Freeman, Alexandra LJ [0000-0002-4115-161X]
Subjects: 0301 basic medicine, Research Report, Applied psychology, MEDLINE, 030105 genetics & heredity, 03 medical and health sciences, risk communication, Surveys and Questionnaires, Cystic fibrosis carrier, Genetics, Humans, Clinical care, Genetics (clinical), user-centered design, User-centered design, genetic test reports, business.industry, Communication, article, Correction, Usability, personalized medicine, Clinical Practice, Comprehension, 030104 developmental biology, Case-Control Studies, FOS: Biological sciences, Risk probability, Psychology, business
Abstract: Purpose: Guidelines recommend that genetic reports should be clear to nonspecialists, including patients. We investigated the feasibility of creating reports for cystic fibrosis carrier testing through a rapid user-centered design process that built on a previously developed generic template. We evaluated the new reports’ communication efficacy and effects on comprehension against comparable reports used in current clinical practice. Methods: Thirty participants took part in three rounds of interviews. Usability problems were identified and rectified in each round. One hundred ninety-three participants took part in an evaluation of the resulting reports measuring subjective comprehension, risk probability comprehension, perceived communication efficacy, and other factors, as compared with standard reports. Results: Participants viewing the user-centered reports rated them as clearer, easier to understand, and more effective at communicating key information than standard reports. Both groups ended up with equivalent knowledge of risk probabilities, although we observed differences in how those probabilities were perceived. Conclusion: Our findings demonstrate that by starting with a patient-friendly generic report template and modifying it for specific scenarios with a rapid user-centered design process, reports can be produced that are more effective at communicating key information. The resulting reports are now being implemented into clinical care.
Published: 2019
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31. Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative

Author: Christoffer Nellåker, Fowzan S. Alkuraya, Gareth Baynam, Raphael A. Bernier, Francois P.J. Bernier, Vanessa Boulanger, Michael Brudno, Han G. Brunner, Jill Clayton-Smith, Benjamin Cogné, Hugh J.S. Dawkins, Bert B.A. deVries, Sofia Douzgou, Tracy Dudding-Byth, Evan E. Eichler, Michael Ferlaino, Karen Fieggen, Helen V. Firth, David R. FitzPatrick, Dylan Gration, Tudor Groza, Melissa Haendel, Nina Hallowell, Ada Hamosh, Jayne Hehir-Kwa, Marc-Phillip Hitz, Mark Hughes, Usha Kini, Tjitske Kleefstra, R Frank Kooy, Peter Krawitz, Sébastien Küry, Melissa Lees, Gholson J. Lyon, Stanislas Lyonnet, Julien L. Marcadier, Stephen Meyn, Veronika Moslerová, Juan M. Politei, Cathryn C. Poulton, F Lucy Raymond, Margot R.F. Reijnders, Peter N. Robinson, Corrado Romano, Catherine M. Rose, David C.G. Sainsbury, Lyn Schofield, Vernon R. Sutton, Marek Turnovec, Anke Van Dijck, Hilde Van Esch, Andrew O.M. Wilkie, The Minerva Consortium, Minerva Consortium, MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
Subjects: 0301 basic medicine, medicine.medical_specialty, phenotyping, lcsh:QH426-470, Emerging technologies, data sharing, Big data, GENOMES, rare disease, PHENOTYPE, THERAPY, Data governance, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, FACIAL DYSMORPHOLOGY, RARE, Policy and Practice Reviews, Health care, medicine, Facial features, Genetics, Data Protection Act 1998, Faces, MATCHMAKER EXCHANGE, Genetics (clinical), Genetics & Heredity, data protection, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Science & Technology, business.industry, Public health, RECOGNITION, Public good, Data science, patient information, 3. Good health, GENOTYPE, Data sharing, lcsh:Genetics, INDIVIDUALS, 030104 developmental biology, DE-NOVO MUTATIONS, 030220 oncology & carcinogenesis, Molecular Medicine, Human medicine, business, Life Sciences & Biomedicine, Consortium
Abstract: The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health. ispartof: FRONTIERS IN GENETICS vol:10 ispartof: location:Switzerland status: published
Published: 2019

32. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author: Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Published: 2019
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33. Systematic re-annotation of 191 genes associated with early-onset epilepsy unmasks de novo variants linked to Dravet syndrome in novel SCN1A exons

Author: Stephen Abbs, Caroline Nava, Sanjay M. Sisodiya, Jyoti S. Choudhary, Dimitrios Vitsios, Dmitri D. Pervouchine, Electra Tapanari, Fadi F. Hamdan, Hannah Stamberger, Berten Ceulemans, Detelina Grozeva, Jennifer Harrow, Patricia Leroy, Marie Marthe Suner, Charles A. Steward, Gianpiero L. Cavalleri, Margarida Viola, Anne Fabienne Lepine, José M. González, Mark Diekhans, Barbara Uszczynska-Ratajczak, Paul Flicek, Nicholas Lench, F. Lucy Raymond, Adam Frankish, Robert Petryszak, Stephen Fitzgerald, Sarah Weckhuysen, Alba Sanchis-Juan, James C. Wright, Peter De Jonghe, Roderic Guigó, Anthony Rogers, Slavé Petrovski, Don Keiller, Jonathan M. Mudge, Jolien Roovers, and Berge A. Minassian
Subjects: Genetics, 0303 health sciences, GENCODE, Gene Annotation, Biology, medicine.disease, Genome, 3. Good health, 03 medical and health sciences, Exon, 0302 clinical medicine, Dravet syndrome, Genotype, medicine, Exome, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The early infantile epileptic encephalopathies (EIEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 novel putative transcript models. The extended transcriptional footprint of these genes allowed for 294 intronic or intergenic variants, found in human mutation databases, to be reclassified as exonic, while a further 70 intronic variants were reclassified as splice-site proximal. Using SCN1A as a case study due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome, or a similar phenotype, with a panel of novel exon sequences representing eight established genes and identified two de novo SCN1A variants that now, through improved gene annotation can be ascribed to residing among novel exons. These two (from 122 screened patients, 1.6%) new molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously-classified SCN1A intronic Dravet-associated variant that now lies within a deeply conserved novel exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders. We would expect to find new molecular diagnoses in our 191 genes that were originally suspected by clinicians for patients, with a negative diagnosis.
Published: 2019
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34. Correction: Psychiatric disorders in children with 16p11.2 deletion and duplication

Author: Jeremy Hall, Ellen Hanson, Sébastien Jacquemont, David Edmund Johannes Linden, Maria Niarchou, Anne M. Maillard, F. Lucy Raymond, Wendy K. Chung, David Skuse, Marianne Bernadette van den Bree, Joanne L. Doherty, LeeAnne Green-Snyder, Samuel J.R.A. Chawner, Stefanie C. Linden, Michael John Owen, Raphael Bernier, and Robin P. Goin-Kochel
Subjects: Male, 0301 basic medicine, Heterozygote, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Autism Spectrum Disorder, computer.internet_protocol, MEDLINE, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Chromosome Duplication, Gene duplication, medicine, Humans, Child, Psychiatry, Biological Psychiatry, Sequence Deletion, Correction, Psychiatry and Mental health, 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Child, Preschool, Female, Citation, Psychology, computer, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery, XML
Abstract: Deletion and duplication of 16p11.2 (BP4–BP5) have been associated with an increased risk of intellectual disability and psychiatric disorder. This is the first study to compare the frequency of a broad spectrum of psychiatric disorders in children with 16p11.2 deletion and duplication. We aimed to evaluate (1) the nature and prevalence of psychopathology associated with copy number variation (CNV) in children with 16p11.2 by comparing deletion and duplication carriers with family controls; (2) whether deletion and duplication carriers differ in frequency of psychopathology. 217 deletion carriers, 77 deletion family controls, 114 duplication carriers, and 32 duplication family controls participated in the study. Measures included standardized research diagnostic instruments. Deletion carriers had a higher frequency of any psychiatric disorder (OR = 8.9, p
Published: 2019
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35. Rare Genetic Variation in 135 Families With Family History Suggestive of X-Linked Intellectual Disability

Author: Olivera Spasic-Boskovic, F. Lucy Raymond, Christina Bitsara, Keren J. Carss, Joanna Jarvis, Kay Yi Low, Courtney E. French, Alba Sanchis-Juan, Michael Field, Detelina Grozeva, French, Courtney [0000-0001-7620-1544], Raymond, Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, lcsh:QH426-470, X-linked intellectual disability, Disease, Biology, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, Genetic variation, autosomal dominant, medicine, Genetics, Family history, Genetics (clinical), Phenocopy, X-linked, Genetic heterogeneity, Inheritance (genetic algorithm), Brief Research Report, medicine.disease, lcsh:Genetics, 030104 developmental biology, mosaicism, intellectual disability, 030220 oncology & carcinogenesis, Molecular Medicine, next-generation sequencing, Mendelian disease
Abstract: Families with multiple male children with intellectual disability (ID) are usually suspected of having disease due to a X-linked mode of inheritance and genetic studies focus on analysis of segregating variants in X-linked genes. However, the genetic cause of ID remains elusive in approximately 50% of affected individuals. Here, we report the analysis of next-generation sequencing data in 274 affected individuals from 135 families with a family history suggestive of X-linked ID. Genetic diagnoses were obtained for 19% (25/135) of the families, and 24% (33/135) had a variant of uncertain significance. In 12% of cases (16/135), the variants were not shared within the family, suggesting genetic heterogeneity and phenocopies are frequent. Of all the families with reportable variants (43%, 58/135), we observed that 55% (32/58) were in X-linked genes, but 38% (22/58) were in autosomal genes, while the remaining 7% (4/58) had multiple variants in genes with different modes on inheritance. This study highlights that in families with multiple affected males, X linkage should not be assumed, and both individuals should be considered, as different genetic etiologies are common in apparent familial cases.
Published: 2019

36. Genotype-phenotype relationships in children with copy number variants associated with high neuropsychiatric risk: Findings from the Intellectual Disability & Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study

Author: Lucy Raymond, David Skuse, Michael John Owen, Peter Holmans, Marianne Bernadette van den Bree, Samuel J.R.A. Chawner, and Jeremy Hall
Subjects: medicine.diagnostic_test, business.industry, Context (language use), Cognition, 030227 psychiatry, 03 medical and health sciences, 0302 clinical medicine, Mood, mental disorders, medicine, Trait, Anxiety, Copy-number variation, medicine.symptom, business, 030217 neurology & neurosurgery, Clinical psychology, Psychopathology, Genetic testing
Abstract: BackgroundA variety of copy number variants are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Different ND-CNVs could lead to distinct and specific patterns of cognitive and behavioural outcomes, but supporting evidence is currently lacking.Methods258 children with ND-CNVs (13 CNVs across 9 loci) were systematically assessed for psychiatric disorders as well as broader traits of neurodevelopmental, cognitive and psychopathological origin. A comparison was made with 106 non-carrier control siblings, in order to test the hypothesis that phenotypes would differ by genotype, both quantitatively, in terms of severity, and qualitatively in the pattern of associated impairments.Outcomes79.8% of ND-CNVs carriers met criteria for one or more psychiatric disorders (OR=13.8 compared to controls): the risk of ADHD (OR=6.9), ODD (OR=3.6), anxiety disorders (OR=2.9), and ASD traits (OR=44.1) was particularly high. ND-CNVs carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits relative to controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. In general, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, however the specific genotype accounted for a low proportion of variance in outcome (5-20% depending on trait).InterpretationThe 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Our findings suggest that genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits, and provides important implications for research into genotype-phenotype relationships within psychiatry.FundingThe Medical Research Council and the Medical Research FoundationResearch in contextEvidence before this studySeveral copy number variants (CNVs) have been associated with high risk of development of child and adult neuropsychiatric disorders. Increasingly young children with developmental delay referred for genetic testing are being diagnosed with neurodevelopmental and psychiatric risk CNVs (referred to as ND-CNVs hereafter). It remains unclear whether different genotypes are associated with specific cognitive and behavioural phenotypes or whether these outcomes are non-specific. We searched PubMed for studies published from database inception until January 10th, 2019 that investigated the relationship between CNVs and cognitive and behavioural outcomes. Search terms included “CNV”, “genomics”, “1q21.1”, “2p16.3”, “NRXN1”, “9q34”, “Kleefstra Syndrome”, “15q11.2”, “15q13.3”, “16p11.2”, “22q11.2”, “psychiatry”, and “cognition”. Preliminary studies have indicated that deletions and duplications at the same loci may differ in cognitive and behavioural phenotypes. However, to date, there have been limited studies that contrasted the phenotypes of ND-CNVs across several loci on a range of cognitive and behavioural domains.Added value of this studyWe found that young people carrying a ND-CNV were at considerably increased risk for neuropsychiatric disorder and impairments across a range of neurodevelopmental, psychopathological, cognitive, social, sleep and motor traits. Within ND-CNV carriers, comparisons between genotypes indicated moderate quantitative and qualitative differences in overall phenotypic profile, with evidence that severity of impairment was similar across all genotypes for some traits (e.g. mood problems, sleep impairments, peer problems, and sustained attention) whereas for other traits there was evidence of genotype specific effects on severity (e.g., IQ, spatial planning, processing speed, subclinical psychotic experiences, ASD traits, motor coordination total psychiatric symptomatology, particularly anxiety, ADHD, and conduct related traits). However the proportion of variance explained by genotype was low, 5-20% depending on trait, indicating that overall ND-CNVs lead to similar neurodevelopmental outcomes. It is important that genotype-phenotype relationships are viewed through a developmental lens as some phenotypic outcomes were found to be associated with age.Implications of all the available evidenceChildren who carry a ND-CNV represent a patient group that warrants clinical and educational attention for a broad range of cognitive and behavioural impairments. Although qualitative and quantitative differences exist between ND-CNVs, our findings point to commonalities in clinical outcomes with neurodevelopmental impairments being present across all ND-CNVs. This group of young people could benefit from the development of a general intervention plan, to which genotype-specific recommendations can be added where needed. Our findings do not support a model whereby different ND-CNVs represent discrete forms of neuropsychiatric disorder and suggest that multiple processes and neural circuits are affected by ND-CNVs. The pleiotropic effects of ND-CNVs emphasises that research aiming to identify causal pathways between genetic variation and psychiatric outcomes via intermediary (or endo-)phenotypes needs to take a global perspective and not be narrowly focused on single phenotypes.
Published: 2019
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37. Whole-genome sequencing of rare disease patients in a national healthcare system

Author: William J. Astle, F. Lucy Raymond, Kathleen Freson, Willem H. Ouwehand, Karyn Megy, Kathleen Stirrups, and Ernest Turro
Subjects: Whole genome sequencing, Genetics, 0303 health sciences, Disease, Biology, Genome, 3. Good health, LRBA, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, 030220 oncology & carcinogenesis, Mendelian inheritance, symbols, Allele, Gene, 030304 developmental biology, Rare disease
Abstract: Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered. We implemented whole-genome sequencing (WGS) in a national healthcare system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank1, we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
Published: 2019
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38. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

Author: Stephen Abbs, Dimitrios Vitsios, Dmitri D. Pervouchine, Paul Flicek, Hannah Stamberger, Roderic Guigó, Barbara Uszczynska-Ratajczak, F. Lucy Raymond, Margarida Viola, Jennifer Harrow, Adam Frankish, Robert Petryszak, Sarah Weckhuysen, Alba Sanchis-Juan, Caroline Nava, Electra Tapanari, José M. González, Anthony Rogers, Slavé Petrovski, Anne Fabienne Lepine, Patricia Leroy, Detelina Grozeva, Marie Marthe Suner, Mark Diekhans, Gianpiero L. Cavalleri, Don Keiller, Berten Ceulemans, Nicholas Lench, Jonathan M. Mudge, Jolien Roovers, Stephen Fitzgerald, Berge A. Minassian, Charles A. Steward, Peter De Jonghe, Sanjay M. Sisodiya, Fadi F. Hamdan, Steward, Charles A [0000-0001-8829-5349], Suner, Marie-Marthe [0000-0002-0380-7171], Uszczynska-Ratajczak, Barbara [0000-0003-0150-3841], Viola, Margarida [0000-0001-6577-3520], Diekhans, Mark [0000-0002-0430-0989], Vitsios, Dimitrios [0000-0002-8939-5445], Flicek, Paul [0000-0002-3897-7955], Apollo - University of Cambridge Repository, and Steward, Charles A. [0000-0001-8829-5349]
Subjects: 0301 basic medicine, lcsh:QH426-470, lcsh:Medicine, Biology, Genome, 03 medical and health sciences, Exon, 0302 clinical medicine, Dravet syndrome, Genetics, medicine, Molecular Biology, Gene, Exome, Genetics (clinical), 631/61/212/2301, Molecular medicine, GENCODE, lcsh:R, article, Gene Annotation, medicine.disease, Phenotype, 692/4017, 3. Good health, lcsh:Genetics, 030104 developmental biology, Human medicine, Medical genomics, 030217 neurology & neurosurgery
Abstract: The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60–65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional ‘footprint’ of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.
Published: 2019

39. Dysregulations of sonic hedgehog signaling in MED12‐related X‐linked intellectual disability disorders

Author: Melanie M. May, Jozef Gecz, Patrick S. Tarpey, Annick Toutain, Pierre-Simon Jouk, Slyvain Briault, Lucy Raymond, Cindy Skinner, William Allen, Roger E. Stevenson, Anna Hackett, William Heath, Tao Wang, Tejasvi Niranjan, Siddharth Srivastava, and Charles E. Schwartz
Subjects: 0301 basic medicine, Adult, Male, X-linked intellectual disability, Mutation, Missense, Nerve Tissue Proteins, Bone Morphogenetic Protein 4, 030105 genetics & heredity, Biology, Cyclic AMP Response Element-Binding Protein A, MED12, Craniofacial Abnormalities, 03 medical and health sciences, Protein Domains, Shh signaling, Genetics, medicine, Basic Helix-Loop-Helix Transcription Factors, Humans, Hedgehog Proteins, Molecular Biology, Genetics (clinical), Cells, Cultured, Mediator Complex, XLID, Original Articles, qRT‐PCR, Middle Aged, medicine.disease, Hedgehog signaling pathway, Pedigree, 030104 developmental biology, Mutation (genetic algorithm), Mutation, Mental Retardation, X-Linked, SHH Signaling, Original Article, Human medicine, Signal Transduction
Abstract: Background Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X‐linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3‐dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH‐signaling defects related to the complex clinical phenotype of MED12‐associated XLID syndromes are not fully understood. Methods Quantitative RT‐PCR was used to study expression levels of three SHH‐signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. Results Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS‐domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L‐domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3‐dependent SHH‐signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT‐PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12‐LS domain. Conclusions These results support a critical role of MED12 in regulating Gli3‐dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH‐signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12‐related XLID disorders.
Published: 2019

40. Eight further individuals with intellectual disability and epilepsy carrying bi-allelicCNTNAP2aberrations allow delineation of the mutational and phenotypic spectrum

Author: Christiane Zweier, Valérie Benoit, Alejandro Leal, Marie-Cécile Nassogne, Lucy Raymond, Marie Deprez, Mateja Smogavec, Alison Cleall, Damien Lederer, Elizabeth E. Palmer, Jozef Gecz, Deborah J. Shears, Marie Shaw, Charlotte Noakes, Knut Brockmann, Isabelle Maystadt, Juliane Hoyer, and André Reis
Subjects: Adult, Male, 0301 basic medicine, CNTNAP2, Adolescent, DNA Copy Number Variations, DNA Mutational Analysis, Nerve Tissue Proteins, Biology, Compound heterozygosity, Craniofacial Abnormalities, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Allele, Child, Alleles, Genetics (clinical), Infant, Membrane Proteins, Syndrome, Middle Aged, Cortical dysplasia, medicine.disease, Pedigree, 3. Good health, Malformations of Cortical Development, Phenotype, 030104 developmental biology, Child, Preschool, Mutation, Female, Epilepsies, Partial, 030217 neurology & neurosurgery
Abstract: Background Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum. Methods Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy. Results We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one. Conclusions By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2 .
Published: 2016
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41. Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

Author: Karyn Megy, Nicholas Gleadall, Christopher E. French, Ricardo Garcia Branco, Marie Erwood, Topun Austin, Olga Shamardina, Willem H. Ouwehand, Helen Dolling, F Lucy Raymond, Alba Sanchis-Juan, Luca Stefanucci, Keren J. Carss, Jonathan Stephens, Eleanor Dewhurst, Trevor Cole, Christopher J. Penkett, Isabelle Delon, Detelina Grozeva, Kathleen Stirrups, Andrew R. Webster, Gavin Arno, Stephens, Jonathan [0000-0003-2020-9330], French, Courtney [0000-0001-7620-1544], Shamardina, Olga [0000-0003-4994-2157], Johnson, Kathleen [0000-0002-6823-3252], Dolling, Helen [0000-0001-6279-3622], Stefanucci, Luca [0000-0002-4352-1151], Austin, Topun [0000-0002-8428-8624], Ouwehand, Willem [0000-0002-7744-1790], Raymond, Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Nanopore, Male, lcsh:QH426-470, Systems biology, CDKL5, lcsh:Medicine, Cell Cycle Proteins, Heterogeneous-Nuclear Ribonucleoprotein U, Biology, Protein Serine-Threonine Kinases, Genome sequencing, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Genetics, CEP78, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Genetics (clinical), Genome, Human, Research, Breakpoint, lcsh:R, Complex structural variant, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Human genetics, ARID1B, DNA-Binding Proteins, lcsh:Genetics, 030104 developmental biology, HNRNPU, Genomic Structural Variation, Mutation, Next-generation sequencing, Molecular Medicine, Identification (biology), Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Background Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. Methods We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. Results We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. Conclusions Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation. Electronic supplementary material The online version of this article (10.1186/s13073-018-0606-6) contains supplementary material, which is available to authorized users.
Published: 2018

42. Whole genome sequencing reveals novel mutations causing autosomal dominant inherited macular degeneration

Author: Shyamanga Borooah, Gavin Arno, Pooja Biswas, Naushin Waseem, Lucy Raymond, Keren J. Carss, Georgios Agorogiannis, Andrew R. Webster, Joseph A. Marsh, and Chloe M. Stanton
Subjects: 0301 basic medicine, Male, genetic structures, DNA Mutational Analysis, Mutation, Missense, Visual Acuity, Biology, Polymerase Chain Reaction, Nyctalopia, 03 medical and health sciences, Macular Degeneration, 0302 clinical medicine, medicine, Electroretinography, Humans, Fluorescein Angiography, Genetics (clinical), Aged, Genes, Dominant, Genetics, Whole genome sequencing, Tissue Inhibitor of Metalloproteinase-3, Whole Genome Sequencing, Macular dystrophy, Macular degeneration, Middle Aged, medicine.disease, eye diseases, Pedigree, Ophthalmology, 030104 developmental biology, Pediatrics, Perinatology and Child Health, 030221 ophthalmology & optometry, Female, sense organs, Collagen, medicine.symptom, Tomography, Optical Coherence
Abstract: BACKGROUND: Age-related macular degeneration (AMD) is a common sight threatening condition. However, there are a number of monogenic macular dystrophies that are clinically similar to AMD, which can potentially provide pathogenetic insights.METHODS: Three siblings from a non-consanguineous Greek-Cypriot family reported central visual disturbance and nyctalopia. The patients had full ophthalmic examinations and color fundus photography, spectral-domain ocular coherence tomography and scanning laser ophthalmoscopy. Targeted polymerase chain reaction (PCR) was performed as a first step to attempt to identify suspected mutations in C1QTNF5 and TIMP3 followed by whole genome sequencing.RESULTS: The three patients were noted to have symptoms of nyctalopia, early paracentral visual field loss and, in older patients, central vision loss. Imaging identified pseudodrusen, retinal atrophy and RPE-Bruch's membrane separation. Whole genome sequencing of the proband revealed two novel heterozygous variants in C1QTNF5, c.556C>T, and c.569C>G. The mutation segregated with disease in this family, occurred in cis, and resulted in missense amino acid changes P186S and S190W in C1QTNF5. In silico modeling of the variants revealed that the S190W mutations was likely to have the greatest pathologic effect and that the combination of the mutations was likely to have an additive effect.CONCLUSIONS: The novel mutations in C1QTNF5 identified here expand the genotypic spectrum of mutations causing late-onset retinal dystrophy.
Published: 2018
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43. De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures

Author: Yoko Ito, Keren J. Carss, Sofia T. Duarte, Taila Hartley, Boris Keren, Manju A. Kurian, Isabelle Marey, Perinne Charles, Carla Mendonça, Caroline Nava, Rolph Pfundt, Alba Sanchis-Juan, Hans van Bokhoven, Anthony van Essen, Conny van Ravenswaaij-Arts, Kym M. Boycott, Kristin D. Kernohan, Sarah Dyack, F. Lucy Raymond, Timothy Aitman, David Bennett, Mark Caulfield, Patrick Chinnery, Daniel Gale, Ania Koziell, Taco W. Kuijpers, Michael A. Laffan, Eamonn Maher, Hugh S. Markus, Nicholas W. Morrell, Willem H. Ouwehand, David J. Perry, Irene Roberts, Kenneth G.C. Smith, Adrian Thrasher, Hugh Watkins, Catherine Williamson, Geoffrey Woods, Sofie Ashford, John R. Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Christopher J. Penkett, Kathleen Stirrups, Marijke Veltman, Tim Young, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Amy Frary, Rachel Linger, Jennifer M. Martin, Sofia Papadia, Karola Rehnstrom, Hannah Stark, David Allsup, Steve Austin, Tamam Bakchoul, Tadbir K. Bariana, Paula Bolton-Maggs, Elizabeth Chalmers, Janine Collins, Peter Collins, Wendy N. Erber, Tamara Everington, Remi Favier, Kathleen Freson, Bruce Furie, Michael Gattens, Johanna Gebhart, Keith Gomez, Daniel Greene, Andreas Greinacher, Paolo Gresele, Daniel Hart, Johan W.M. Heemskerk, Yvonne Henskens, Rashid Kazmi, David Keeling, Anne M. Kelly, Michele P. Lambert, Claire Lentaigne, Ri Liesner, Mike Makris, Sarah Mangles, Mary Mathias, Carolyn M. Millar, Andrew Mumford, Paquita Nurden, Jeanette Payne, John Pasi, Kathelijne Peerlinck, Shoshana Revel-Vilk, Michael Richards, Matthew Rondina, Catherine Roughley, Sol Schulman, Harald Schulze, Marie Scully, Suthesh Sivapalaratnam, Matthew Stubbs, R. Campbell Tait, Kate Talks, Jecko Thachil, Cheng-Hock Toh, Ernest Turro, Chris Van Geet, Minka De Vries, Timothy Q. Warner, Henry Watson, Sarah Westbury, Abigail Furnell, Rutendo Mapeta, Paula Rayner-Matthews, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Christopher Watt, Deborah Whitehorn, Antony Attwood, Louise Daugherty, Sri V.V. Deevi, Csaba Halmagyi, Fengyuan Hu, Vera Matser, Stuart Meacham, Karyn Megy, Olga Shamardina, Catherine Titterton, Salih Tuna, Ping Yu, Julie von Ziegenweldt, William Astle, Marta Bleda, Stefan Gräf, Matthias Haimel, Hana Lango-Allen, Sylvia Richardson, Paul Calleja, Stuart Rankin, Wojciech Turek, Julie Anderson, Christine Bryson, Jenny Carmichael, Coleen McJannet, Sophie Stock, Louise Allen, Gautum Ambegaonkar, Ruth Armstrong, Gavin Arno, Maria Bitner-Glindzicz, Angie Brady, Natalie Canham, Manali Chitre, Emma Clement, Virginia Clowes, Patrick Deegan, Charu Deshpande, Rainer Doffinger, Helen Firth, Frances Flinter, Courtney French, Alice Gardham, Neeti Ghali, Paul Gissen, Detelina Grozeva, Robert Henderson, Anke Hensiek, Simon Holden, Muriel Holder, Susan Holder, Jane Hurst, Dragana Josifova, Deepa Krishnakumar, Melissa Lees, Robert MacLaren, Anna Maw, Sarju Mehta, Michel Michaelides, Anthony Moore, Elaine Murphy, Soo-Mi Park, Alasdair Parker, Chris Patch, Joan Paterson, Julia Rankin, Evan Reid, Elisabeth Rosser, Richard Sandford, Saikat Santra, Richard Scott, Aman Sohal, Penelope Stein, Ellen Thomas, Dorothy Thompson, Marc Tischkowitz, Julie Vogt, Emma Wakeling, Evangeline Wassmer, Andrew Webster, Sonia Ali, Souad Ali, Harm J. Boggard, Colin Church, Gerry Coghlan, Victoria Cookson, Paul A. Corris, Amanda Creaser-Myers, Rosa DaCosta, Natalie Dormand, Mélanie Eyries, Henning Gall, Pavandeep K. Ghataorhe, Stefano Ghio, Ardi Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Alan Greenhalgh, Charaka Hadinnapola, Arjan C. Houweling, Marc Humbert, Anna Huis in’t Veld, Fiona Kennedy, David G. Kiely, Gabor Kovacs, Allan Lawrie, Rob V. Mackenzie Ross, Rajiv Machado, Larahmie Masati, Sharon Meehan, Shahin Moledina, David Montani, Shokri Othman, Andrew J. Peacock, Joanna Pepke-Zaba, Val Pollock, Gary Polwarth, Lavanya Ranganathan, Christopher J. Rhodes, Kevin Rue-Albrecht, Gwen Schotte, Debbie Shipley, Florent Soubrier, Laura Southgate, Laura Scelsi, Jay Suntharalingam, Yvonne Tan, Mark Toshner, Carmen M. Treacy, Richard Trembath, Anton Vonk Noordegraaf, Sara Walker, Ivy Wanjiku, John Wharton, Martin Wilkins, Stephen J. Wort, Katherine Yates, Hana Alachkar, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Claire Booth, Michael Browning, Siobhan Burns, Anita Chandra, Nichola Cooper, Sophie Davies, Lisa Devlin, Elizabeth Drewe, David Edgar, William Egner, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Aarnoud Huissoon, Stephen Jolles, Peter Kelleher, Dinakantha Kumararatne, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Sai Murng, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewell, Emily Staples, Hans Stauss, James Thaventhiran, Moira Thomas, Steve Welch, Lisa Willcocks, Nigel Yeatman, Patrick Yong, Phil Ancliff, Christian Babbs, Mark Layton, Eleni Louka, Simon McGowan, Adam Mead, Noémi Roy, Jenny Chambers, Peter Dixon, Cecelia Estiu, Bill Hague, Hanns-Ulrich Marschall, Michael Simpson, Sam Chong, Ingrid Emmerson, Lionel Ginsberg, David Gosal, Rob Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary Reilly, Tara Renton, Andrew Rice, Andreas Themistocleous, Tom Vale, Natalie Van Zuydam, Suellen Walker, Liz Ormondroyd, Gavin Hudson, Wei Wei, Patrick Yu Wai Man, James Whitworth, Maryam Afzal, Elizabeth Colby, Moin Saleem, Omid S. Alavijeh, H. Terry Cook, Sally Johnson, Adam P. Levine, Edwin K.S. Wong, Rhea Tan, Alex MacKenzie, Jacek Majewski, Michael Brudno, Dennis Bulman, David Dyment, Freson, Kathleen, Peerlinck, Kathelijne, Van Geet, Christel, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, Medical Research Council (MRC), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Aging & Later Life, Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, and Molecular cell biology and Immunology
Subjects: 0301 basic medicine, Male, Care4Rare Canada Consortium, WAVE FAMILY PROTEINS, actin cytoskeleton, PROTEIN, HDE NEU PED, medicine.disease_cause, Whole Exome Sequencing, 0302 clinical medicine, Neurodevelopmental disorder, SYNAPTIC PLASTICITY, Intellectual disability, WAVE1 complex, PLASTICITY, EXCHANGE, 11 Medical and Health Sciences, Exome sequencing, Genetics (clinical), seizures, Genetics & Heredity, Genetics, Mutation, WASF1, DENDRITIC SPINES, developmental delay, Female, DISEASE GENE-DISCOVERY, Adult, Heterozygote, GENES, DISORDERS, autism, Biology, ACTIN, 03 medical and health sciences, Young Adult, Seizures, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, PROTRUSIONS, recurrent de novo truncating mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, lamellipodia, neurodevelopmental disorder, Actin remodeling, Heterozygote advantage, NIHR BioResource, 06 Biological Sciences, medicine.disease, Actin cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, WAVE, RETARDATION, 030217 neurology & neurosurgery
Abstract: Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published
Published: 2018
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44. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author: Katherine L. Helbig, Robert J. Lauerer, Jacqueline C. Bahr, Ivana A. Souza, Candace T. Myers, Betül Uysal, Niklas Schwarz, Maria A. Gandini, Sun Huang, Boris Keren, Cyril Mignot, Alexandra Afenjar, Thierry Billette de Villemeur, Delphine Héron, Caroline Nava, Stéphanie Valence, Julien Buratti, Christina R. Fagerberg, Kristina P. Soerensen, Maria Kibaek, Erik-Jan Kamsteeg, David A. Koolen, Boudewijn Gunning, H. Jurgen Schelhaas, Michael C. Kruer, Jordana Fox, Somayeh Bakhtiari, Randa Jarrar, Sergio Padilla-Lopez, Kristin Lindstrom, Sheng Chih Jin, Xue Zeng, Kaya Bilguvar, Antigone Papavasileiou, Qinghe Xing, Changlian Zhu, Katja Boysen, Filippo Vairo, Brendan C. Lanpher, Eric W. Klee, Jan-Mendelt Tillema, Eric T. Payne, Margot A. Cousin, Teresa M. Kruisselbrink, Myra J. Wick, Joshua Baker, Eric Haan, Nicholas Smith, Azita Sadeghpour, Erica E. Davis, Nicholas Katsanis, Mark A. Corbett, Alastair H. MacLennan, Jozef Gecz, Saskia Biskup, Eva Goldmann, Lance H. Rodan, Elizabeth Kichula, Eric Segal, Kelly E. Jackson, Alexander Asamoah, David Dimmock, Julie McCarrier, Lorenzo D. Botto, Francis Filloux, Tatiana Tvrdik, Gregory D. Cascino, Sherry Klingerman, Catherine Neumann, Raymond Wang, Jessie C. Jacobsen, Melinda A. Nolan, Russell G. Snell, Klaus Lehnert, Lynette G. Sadleir, Britt-Marie Anderlid, Malin Kvarnung, Renzo Guerrini, Michael J. Friez, Michael J. Lyons, Jennifer Leonhard, Gabriel Kringlen, Kari Casas, Christelle M. El Achkar, Lacey A. Smith, Alexander Rotenberg, Annapurna Poduri, Alba Sanchis-Juan, Keren J. Carss, Julia Rankin, Adam Zeman, F. Lucy Raymond, Moira Blyth, Bronwyn Kerr, Karla Ruiz, Jill Urquhart, Imelda Hughes, Siddharth Banka, Ulrike B.S. Hedrich, Ingrid E. Scheffer, Ingo Helbig, Gerald W. Zamponi, Holger Lerche, Heather C. Mefford, Alexander Allori, Misha Angrist, Patricia Ashley, Margarita Bidegain, Brita Boyd, Eileen Chambers, Heidi Cope, C. Michael Cotten, Theresa Curington, Sarah Ellestad, Kimberley Fisher, Amanda French, William Gallentine, Ronald Goldberg, Kevin Hill, Sujay Kansagra, Sara Katsanis, Joanne Kurtzberg, Jeffrey Marcus, Marie McDonald, Mohammed Mikati, Stephen Miller, Amy Murtha, Yezmin Perilla, Carolyn Pizoli, Todd Purves, Sherry Ross, Edward Smith, and John Wiener
Subjects: Male, 0301 basic medicine, Movement disorders, Task Force for Neonatal Genomics, Contracture/genetics, Neurodegenerative, Bioinformatics, Neurodevelopmental Disorders/genetics, Infantile, Medical and Health Sciences, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Epilepsy/genetics, Spasms, Epilepsy, Spasms, Infantile/genetics, 0302 clinical medicine, R-Type, 2.1 Biological and endogenous factors, Megalencephaly, Aetiology, Child, Cation Transport Proteins, Genetics (clinical), Pediatric, Genetics & Heredity, Arthrogryposis, 0303 health sciences, Voltage-dependent calcium channel, Epileptic encephalopathy, Deciphering Developmental Disorders Study, Biological Sciences, Hypotonia, 3. Good health, CACNA1E, Genetic Variation/genetics, Child, Preschool, Neurological, Female, Megalencephaly/genetics, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Contracture, Adolescent, Dyskinesias/genetics, Biology, Article, arthrogryposis, 03 medical and health sciences, Genetics, medicine, Humans, Preschool, Calcium Channels, R-Type/genetics, 030304 developmental biology, Muscle contracture, Dyskinesias, business.industry, Calcium channel, Cation Transport Proteins/genetics, Neurosciences, Macrocephaly, Genetic Variation, Correction, Infant, medicine.disease, Human genetics, Brain Disorders, 030104 developmental biology, Neurodevelopmental Disorders, ion channel, calcium channel, Calcium Channels, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: Item does not contain fulltext Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
Published: 2018
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45. SYT1-associated neurodevelopmental disorder: A case series

Author: Fabian Bumbak, Tobias B. Haack, Michael A. Cousin, Michelle D. Amaral, Ingo Borggraefe, Mari Rossi, Mohammed Al-Raqad, Stewart Boyd, Grazia M.S. Mancini, Zornitza Stark, Manju A. Kurian, Daniel Scott, Simon Sadedin, Tiong Yang Tan, Tess J. Jiang, Heike Weigand, Marcella Zollino, Orly Elpeleg, F Lucy Raymond, Yunyun Jiang, Whitley V. Kelley, Sara Ellingwood, David J. Owen, Martina Wilke, Holly Melland, Dawn Peck, Bradley J. Turner, Kate Baker, Giuseppe Marangi, Richard A. Gibbs, Sarah L. Gordon, Baker, Kate [0000-0003-2986-0584], Owen, David [0000-0002-8351-6322], Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, and Clinical Genetics
Subjects: 0301 basic medicine, Male, Action Potentials, Settore MED/03 - GENETICA MEDICA, Synaptic Transmission, Neurotransmitter secretion, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Child, Synaptic vesicle endocytosis, Neurons, Movement Disorders, biology, intellectual disability, movement disorder, synaptic vesicle, synaptotagmin 1, SYT1, Neurology (clinical), Endocytosis, 3. Good health, Child, Preschool, Synaptotagmin I, Female, Synaptic Vesicles, Adolescent, Mutation, Missense, Neurotransmission, Synaptic vesicle, 03 medical and health sciences, Young Adult, medicine, Animals, Humans, Original Articles, medicine.disease, Electrophysiological Phenomena, Rats, Mice, Inbred C57BL, 030104 developmental biology, nervous system, Neurodevelopmental Disorders, Synaptophysin, biology.protein, Calcium, Free nerve ending, Neuroscience, 030217 neurology & neurosurgery
Abstract: Baker, Gordon et al. present the first international case series describing the neurodevelopmental disorder associated with Synaptotagmin 1 (SYT1) de novo missense mutations. Key features include movement abnormalities, severe intellectual disability, and hallmark EEG alterations. Expression of patients’ SYT1 mutations in mouse neurons disturbs presynaptic vesicle dynamics in a mutation-specific manner., Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals’ phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.
Published: 2018
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46. Analysis of Multiple Families With Single Individuals Affected by Pseudohypoparathyroidism Type Ib (PHP1B) Reveals Only One Novel Maternally InheritedGNASDeletion

Author: Agnès Linglart, Tomoyuki Watanabe, Amita Sharma, Monica Reyes, Giedre Grigelioniene, F. Lucy Raymond, Rieko Takatani, Angelo Molinaro, Olta Tafaj, Harald Jüppner, and Vibha Singhal
Subjects: musculoskeletal diseases, 0301 basic medicine, Genetics, biology, Endocrinology, Diabetes and Metabolism, Autosomal dominant trait, 030209 endocrinology & metabolism, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Differentially methylated regions, DNA methylation, GNAS complex locus, biology.protein, Orthopedics and Sports Medicine, STX16, Multiplex ligation-dependent probe amplification, Epigenetics, Allele
Abstract: Proximal tubular resistance to parathyroid hormone (PTH) resulting in hypocalcemia and hyperphosphatemia are preeminent abnormalities in pseudohypoparathyroidism type Ib (PHP1B), but resistance toward other hormones as well as variable features of Albright's Hereditary Osteodystrophy (AHO) can occur also. Genomic DNA from PHP1B patients shows epigenetic changes at one or multiple differentially methylated regions (DMRs) within GNAS, the gene encoding Gαs and splice variants thereof. In the autosomal dominant disease variant, these methylation abnormalities are caused by deletions in STX16 or GNAS on the maternal allele. The molecular defect(s) leading to sporadic PHP1B (sporPHP1B) remains in most cases unknown and we therefore analyzed 60 sporPHP1B patients and available family members by microsatellite markers, single nucleotide polymorphisms (SNPs), multiplex ligation-dependent probe amplification (MLPA), and methylation-specific MLPA (MS-MLPA). All investigated cases revealed broad GNAS methylation changes, but no evidence for inheritance of two paternal chromosome 20q alleles. Some patients with partial epigenetic modifications in DNA from peripheral blood cells showed more complete GNAS methylation changes when testing their immortalized lymphoblastoid cells. Analysis of siblings and children of sporPHP1B patients provided no evidence for an abnormal mineral ion regulation and no changes in GNAS methylation. Only one patient revealed, based on MLPA and microsatellite analyses, evidence for an allelic loss, which resulted in the discovery of two adjacent, maternally inherited deletions (37,597 and 1427 bp, respectively) that remove the area between GNAS antisense exons 3 and 5, including exon NESP. Our findings thus emphasize that the region comprising antisense exons 3 and 4 is required for establishing all maternal GNAS methylation imprints. The genetic defect(s) leading in sporPHP1B to epigenetic GNAS changes and thus PTH-resistance remains unknown, but it seems unlikely that this disease variant is caused by heterozygous inherited or de novo mutations involving GNAS.
Published: 2015
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47. MECP2 missense mutations outside the canonical MBD and TRD domains in males with intellectual disability

Author: Alessandra Renieri, Corrado Romano, Detelina Grozeva, Francesca Mari, Lucy Raymond, Maria Antonietta Mencarelli, Francesca Ariani, Chiara Di Marco, Ilaria Meloni, Marco Fichera, Laura Bianciardi, Ottavia Spiga, and Pinella Failla
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Methyl-CpG-Binding Protein 2, Protein domain, Mutation, Missense, Rett syndrome, Biology, medicine.disease_cause, Bioinformatics, Article, MECP2, 03 medical and health sciences, Protein Domains, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Child, Genetics (clinical), Mutation, Genetic Diseases, X-Linked, medicine.disease, Phenotype, 030104 developmental biology, Statistical genetics, Child, Preschool, Medical genetics, Female
Abstract: Methyl-CpG-binding protein 2 (MeCP2) is a nuclear protein highly expressed in neurons that is involved in transcriptional modulation and chromatin remodeling. Mutations in MECP2 in females are associated with Rett syndrome, a neurological disorder characterized by a normal neonatal period, followed by the arrest of development and regression of acquired skills. Although it was initially thought that MECP2 pathogenic mutations in males were not compatible with life, starting from 1999 about 60 male patients have been identified and their phenotype varies from severe neonatal encephalopathy to mild intellectual disability. Targeted next-generation sequencing of a panel of intellectual disability related genes was performed on two unrelated male patients, and two missense variants in MECP2 were identified (p.Gly185Val and p.Arg167Trp). These variants lie outside the canonical methyl-CpG-binding domain and transcription repression domain domains, where the pathogenicity of missense variants is more difficult to establish. In both families, variants were found in all affected siblings and were inherited from the asymptomatic mother, showing skewed X-chromosome inactivation. We report here the first missense variant located in AT-hook domain 1 and we underline the importance of MECP2 substitutions outside the canonical MeCP2 domains in X-linked intellectual disability.
Published: 2015
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48. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Author: Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J. Davies, Michelle K. Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J. Parker, Julia Rankin, Lisa Robertson, I. Karen Temple, Siddharth Banka, Shelin Adam, Christèle du Souich, Alison M. Elliott, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, Jan M. Friedman, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, V.K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, and Matthew E. . Hurles
Subjects: 0301 basic medicine, ASH1L, Male, Methyltransferase, Adolescent, Histone lysine methylation, KMT5B, Developmental Disabilities, Haploinsufficiency, Biology, Compound heterozygosity, histone lysine methyltransferase, Chromatin remodeling, chromatin remodeling, 03 medical and health sciences, histone lysine demethylase, Report, Genetics, Humans, Child, Genetics (clinical), Regulation of gene expression, Histone Demethylases, Developmental disorders, KMT2C, KMT2B, Histone-Lysine N-Methyltransferase, 030104 developmental biology, Histone, Overgrowth syndrome, Child, Preschool, Mutation, biology.protein, KDM5B, Female
Abstract: Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.
Published: 2017
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49. Impaired oxidative stress response characterizes HUWE1-promoted X-linked intellectual disability

Author: Paul Hoff Backe, F. Lucy Raymond, Matthias Altmeyer, Magnar Bjørås, Vuk Palibrk, Stefania Pellegrino, Guy Froyen, Barbara van Loon, Rossana Aprigliano, Matthias Bosshard, Cristina Gattiker, Grigory L. Dianov, Enni Markkanen, Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, University of Zurich, and van Loon, Barbara
Subjects: 0301 basic medicine, DNA Repair, DNA repair, X-linked intellectual disability, Ubiquitin-Protein Ligases, lcsh:Medicine, medicine.disease_cause, Article, Genomic Instability, Cell Line, 03 medical and health sciences, Neurodevelopmental disorder, Genes, X-Linked, Intellectual Disability, Gene duplication, medicine, Humans, lcsh:Science, Gene, DNA Polymerase beta, Genetics, 1000 Multidisciplinary, Mutation, Multidisciplinary, biology, Tumor Suppressor Proteins, lcsh:R, medicine.disease, 10226 Department of Molecular Mechanisms of Disease, Ubiquitin ligase, Oxidative Stress, 030104 developmental biology, biology.protein, 570 Life sciences, lcsh:Q, Oxidative stress
Abstract: Mutations in the HECT, UBA and WWE domain-containing 1 (HUWE1) E3 ubiquitin ligase cause neurodevelopmental disorder X-linked intellectual disability (XLID). HUWE1 regulates essential processes such as genome integrity maintenance. Alterations in the genome integrity and accumulation of mutations have been tightly associated with the onset of neurodevelopmental disorders. Though HUWE1 mutations are clearly implicated in XLID and HUWE1 regulatory functions well explored, currently much is unknown about the molecular basis of HUWE1-promoted XLID. Here we showed that the HUWE1 expression is altered and mutation frequency increased in three different XLID individual (HUWE1 p.R2981H, p.R4187C and HUWE1 duplication) cell lines. The effect was most prominent in HUWE1 p.R4187C XLID cells and was accompanied with decreased DNA repair capacity and hypersensitivity to oxidative stress. Analysis of HUWE1 substrates revealed XLID-specific down-regulation of oxidative stress response DNA polymerase (Pol) λ caused by hyperactive HUWE1 p.R4187C. The subsequent restoration of Polλ levels counteracted the oxidative hypersensitivity. The observed alterations in the genome integrity maintenance may be particularly relevant in the cortical progenitor zones of human brain, as suggested by HUWE1 immunofluorescence analysis of cerebral organoids. These results provide evidence that impairments of the fundamental cellular processes, like genome integrity maintenance, characterize HUWE1-promoted XLID. © The Author(s) 2017. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Published: 2017
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50. Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Author: Cristy A. Ku, Robert E MacLaren, F. Lucy Raymond, Gavin Arno, Ryan D. Geraets, Sarah Hull, Keren J. Carss, Michel Michaelides, Graham E. Holder, Anthony G. Robson, Andrew R. Webster, Anthony T. Moore, Mark E. Pennesi, Elise Héon, Camille Parker, David A. Pearce, Glenn Anderson, Robert J. Kayton, Ajoy Vincent, and Douglas A. Weeks
Subjects: 0301 basic medicine, Retinal degeneration, Adult, Male, Pathology, medicine.medical_specialty, Visual acuity, Adolescent, DNA Mutational Analysis, Visual Acuity, Disease, Ophthalmoscopy, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Atrophy, medicine, Electroretinography, Humans, Aged, Original Investigation, Membrane Glycoproteins, medicine.diagnostic_test, business.industry, Retinal Degeneration, Dystrophy, Retinal, DNA, Middle Aged, medicine.disease, Pedigree, Ophthalmology, 030104 developmental biology, Phenotype, chemistry, Mutation, 030221 ophthalmology & optometry, Female, medicine.symptom, business, Tomography, Optical Coherence, Molecular Chaperones
Abstract: Importance:Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. Objective:To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. Design, Setting, and Participants:A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. Main Outcomes and Measures:Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. Results:There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses. Conclusions and Relevance:This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.
Published: 2017

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