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1. Identification and analysis of deletion breakpoints in four Mohr-Tranebjærg syndrome (MTS) patients

Author

Nanna Dahl Rendtorff, Helena Gásdal Karstensen, Marianne Lodahl, John Tolmie, Catherine McWilliam, Mads Bak, Niels Tommerup, Lusine Nazaryan-Petersen, Henricus Kunst, Melanie Wong, Shelagh Joss, Valerio Carelli, and Lisbeth Tranebjærg

Subjects
Medicine, Science
Abstract

Abstract Mohr-Tranebjærg syndrome is an X-linked syndrome characterized by sensorineural hearing impairment in childhood, followed by progressive neurodegeneration leading to a broad phenotypic spectrum. Genetically MTS is caused by pathogenic variants in the TIMM8A gene, including gene deletions and larger contiguous gene deletions. Some of the latter involve the neighboring gene BTK, resulting in agammaglobulinemia. By next‐generation mate‐pair sequencing we have mapped the chromosomal deletion breakpoints of one MTS case and three XLA-MTS cases and used breakpoint-spanning PCR to fine map the breakpoints by Sanger sequencing. Two of the XLA-MTS cases presented with large deletions (63.5 and 27.2 kb), and the junctional regions were characterized by long stretches of microhomology, indicating that the events have emerged through homologous recombination. Conversely, the MTS case exhibited a small 2 bp region of microhomology, and the regions were not characterized by extensive microhomology. The third XLA-MTS case had a more complex breakpoint, including a 59 bp inverted insertion, thus at least four breakpoints were involved in this event. In conclusion, mate-pair library generation combined with next-generation sequencing is an efficient method for breakpoint identification, also in regions characterized by repetitive elements.

Published
2022
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2. ‘We have been in lockdown since he was born’: a mixed methods exploration of the experiences of families caring for children with intellectual disability during the COVID-19 pandemic in the UK

Author

Diana Baralle, Susan Walker, Ramya Srinivasan, Shelagh Joss, Jonathan Berg, Miranda Splitt, Usha Kini, Pradeep Vasudevan, John Dean, Yanick Crow, Beverly Searle, Julian Barwell, Lyn Chitty, Peter Holmans, Sarah Law, Virginia Clowes, Rachel Harrison, Muriel Holder, Sahar Mansour, Spiros Denaxas, Ellie Kerry, Frances Flinter, Zheng Ye, Julia Rankin, Oliver Quarrell, Nicola Lewis, Anne Lampe, Astrid Weber, David Skuse, Kate Baker, Annie Procter, Jeremy Hall, Alison Kraus, Neil Walker, Jeanne Wolstencroft, Laura Hull, Lauren Warner, Tooba Nadeem Akhtar, William Mandy, Eleanor Dewhurst, Amy Lafont, F Lucy Raymond, Terry Shirley, Hayley Tilley, Husne Timur, Catherine Titterton, Sarah Wallwork, Francesca Wicks, Marie Erwood, Sophie Andrews, Philippa Birch, Samantha Bowen, Karen Bradley, Aimee Challenger, Samuel Chawner, Andrew Cuthbert, Sinead Morrison, Hayley Moss, Michael Owen, Sinead Ray, Matthew Sopp, Molly Tong, Marianne van den Bree, Nadia Coscini, Hayley Denyer, Nasrtullah Fatih, Manoj Juj, Anna Lucock, Frida Printzlau, Alice Watkins, Anna Pelling, Lisa Robertson, Denise Williams Alan, Donaldson Lucy, and Fleur van Dijk

Subjects
Medicine
Published
2021
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3. Tuberous Sclerosis Complex (TSC): Expert Recommendations for Provision of Coordinated Care

Author

Nicholas M. P. Annear, Richard E. Appleton, Zahabiyah Bassi, Rupesh Bhatt, Patrick F. Bolton, Pamela Crawford, Alex Crowe, Maureen Tossi, Frances Elmslie, Eric Finlay, Daniel P. Gale, Alex Henderson, Elizabeth A. Jones, Simon R. Johnson, Shelagh Joss, Larissa Kerecuk, Graham Lipkin, Patrick J. Morrison, Finbar J. O'Callaghan, Jill Cadwgan, Albert C. M. Ong, Julian R. Sampson, Charles Shepherd, and J. Chris Kingswood

Subjects
tuberous sclerosis complex, service specification, commissioning, surveillance, guidelines, clinics, Neurology. Diseases of the nervous system, RC346-429
Published
2019
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4. Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability

Author

Claudio Reggiani, Sandra Coppens, Tayeb Sekhara, Ivan Dimov, Bruno Pichon, Nicolas Lufin, Marie-Claude Addor, Elga Fabia Belligni, Maria Cristina Digilio, Flavio Faletra, Giovanni Battista Ferrero, Marion Gerard, Bertrand Isidor, Shelagh Joss, Florence Niel-Bütschi, Maria Dolores Perrone, Florence Petit, Alessandra Renieri, Serge Romana, Alexandra Topa, Joris Robert Vermeesch, Tom Lenaerts, Georges Casimir, Marc Abramowicz, Gianluca Bontempi, Catheline Vilain, Nicolas Deconinck, and Guillaume Smits

Subjects
Functional genomics, Promoters, Neurodevelopmental disorders, Intellectual disability, DLG2, Medicine, Genetics, QH426-470
Abstract

Abstract Background Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders. Methods Two pediatric patients with global developmental delay and intellectual disability phenotype underwent array-CGH genetic testing, both showing a partial deletion of the DLG2 gene. From independent human and murine omics datasets, we combined copy number variations, histone modifications, developmental tissue-specific regulation, and protein data to explore the molecular mechanism at play. Results Integrating genomics, transcriptomics, and epigenomics data, we describe two novel DLG2 promoters and coding first exons expressed in human fetal brain. Their murine conservation and protein-level evidence allowed us to produce new DLG2 gene models for human and mouse. These new genic elements are deleted in 90% of 29 patients (public and in-house) showing partial deletion of the DLG2 gene. The patients’ clinical characteristics expand the neurodevelopmental phenotypic spectrum linked to DLG2 gene disruption to cognitive and behavioral categories. Conclusions While protein-coding genes are regarded as well known, our work shows that integration of multiple omics datasets can unveil novel coding elements. From a clinical perspective, our work demonstrates that two new DLG2 promoters and exons are crucial for the neurodevelopmental phenotypes associated with this gene. In addition, our work brings evidence for the lack of cross-annotation in human versus mouse reference genomes and nucleotide versus protein databases.

Published
2017
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5. Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study

Author

Jeanne Wolstencroft, Francesca Wicks, Ramya Srinivasan, Sarah Wynn, Tamsin Ford, Kate Baker, Samuel J R A Chawner, Jeremy Hall, Marianne B M van den Bree, Michael J Owen, David Skuse, F Lucy Raymond, Marie Erwood, Amy Lafont, Husne Timur, Zheng Ye, Susan Walker, Frida Printzlau, Manoj Juj, Sarah Davies, Hayley Denyer, Alice Watkins, Eleanor Kerry, Nadia Coscini, Nasrtullah Fatih, Anna Lucock, Spiros Denaxas, William Mandy, Neil Walker, Sarah Wallwork, Eleanor Dewhurst, Andrew Cuthbert, Aimee Challenger, Sophie Andrews, Peter Holmans, Samantha Bowen, Karen Bradley, Philippa Birch, Molly Tong, Nicola Lewis, Sinead Ray, Matthew Sopp, Hayley Moss, Beverley Searle, Lisa Robertson, Jonathan Berg, Anne Lampe, Shelagh Joss, Paul Brennan, Alison Kraus, Nayana Lahiri, Astrid Weber, Myfanwy Rawson, Diana Johnson, Pradeep Vasudevan, Rachel Harrison, Denise Williams, Eamonn Maher, Usha Kini, Fleur Van Dijk, Virginia Clowes, Jana Gurasashvilli, Sahar Mansour, Muriel Holder-Espinasse, Amy Watford, Julia Rankin, Diana Baralle, Annie Procter, Samuel Chawner, and Marianne B M Van den Bree

Subjects
Male, Adolescent, Autism Spectrum Disorder, State Medicine, United Kingdom, Cohort Studies, Psychiatry and Mental health, Child, Preschool, Intellectual Disability, Humans, Female, Prospective Studies, Child, Biological Psychiatry
Abstract

Background\ud Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population.\ud Methods\ud IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4–19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ.\ud Findings\ud We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9–36·5), ADHD RR 13·5 (95% CI 11·1–16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV.\ud Interpretation\ud Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services.

Published
2022

6. SOX5:Lamb–Shaffer syndrome—A case series further expanding the phenotypic spectrum

Author

Katharine Edgerley, Lisa Bryson, Lucy Hanington, Rachel Irving, Shelagh Joss, Anne Lampe, Isabelle Maystadt, Deborah Osio, Ruth Richardson, Miranda Split, Francis H. Sansbury, Ingrid Scurr, Helen Stewart, Alisdair McNeil, and Karen Low

Subjects
Genetics, Genetics (clinical)
Abstract

To delineate further the clinical phenotype of Lamb–Shaffer Syndrome (LSS) 16 unpublished patients with heterozygous variation in SOX5 were identified either through the UK Decipher database or the study team was contacted by clinicians directly. Clinical phenotyping tables were completed for each patient by their responsible clinical geneticist. Photos and clinical features were compared to assess key phenotypes and genotype–phenotype correlation. We report 16 SOX5 variants all of which meet American College of Medical Genetics/Association for Clinical Genomic Science ACMG/ACGS criteria class IV or V. 7/16 have intragenic deletions of SOX5 and 9/16 have single nucleotide variants (including both truncating and missense variants). The cohort includes two sets of monozygotic twins and parental gonadal mosaicism is noted in one family. This cohort of 16 patients is compared with the 71 previously reported cases and corroborates previous phenotypic findings. As expected, the most common findings include global developmental delay with prominent speech delay, mild to moderate intellectual disability, behavioral abnormalities and sometimes subtle characteristic facial features. We expand in more detail on the behavioral phenotype and observe that there is a greater tendency toward lower growth parameters and microcephaly in patients with single nucleotide variants. This cohort provides further evidence of gonadal mosaicism in SOX5 variants; this should be considered when providing genetic counseling for couples with one affected child and an apparently de novo variant.

Published
2023

7. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Elizabeth E. Palmer, Michael Pusch, Alessandra Picollo, Caitlin Forwood, Matthew H. Nguyen, Vanessa Suckow, Jessica Gibbons, Alva Hoff, Lisa Sigfrid, Andre Megarbane, Mathilde Nizon, Benjamin Cogné, Claire Beneteau, Fowzan S. Alkuraya, Aziza Chedrawi, Mais O. Hashem, Hannah Stamberger, Sarah Weckhuysen, Arnaud Vanlander, Berten Ceulemans, Sulekha Rajagopalan, Kenneth Nunn, Stéphanie Arpin, Martine Raynaud, Constance S. Motter, Catherine Ward-Melver, Katrien Janssens, Marije Meuwissen, Diane Beysen, Nicola Dikow, Mona Grimmel, Tobias B. Haack, Emma Clement, Amy McTague, David Hunt, Sharron Townshend, Michelle Ward, Linda J. Richards, Cas Simons, Gregory Costain, Lucie Dupuis, Roberto Mendoza-Londono, Tracy Dudding-Byth, Jackie Boyle, Carol Saunders, Emily Fleming, Salima El Chehadeh, Marie-Aude Spitz, Amelie Piton, Bénédicte Gerard, Marie-Thérèse Abi Warde, Gillian Rea, Caoimhe McKenna, Sofia Douzgou, Siddharth Banka, Cigdem Akman, Jennifer M. Bain, Tristan T. Sands, Golder N. Wilson, Erin J. Silvertooth, Lauren Miller, Damien Lederer, Rani Sachdev, Rebecca Macintosh, Olivier Monestier, Deniz Karadurmus, Felicity Collins, Melissa Carter, Luis Rohena, Marjolein H. Willemsen, Charlotte W. Ockeloen, Rolph Pfundt, Sanne D. Kroft, Michael Field, Francisco E. R. Laranjeira, Ana M. Fortuna, Ana R. Soares, Vincent Michaud, Sophie Naudion, Sailaja Golla, David D. Weaver, Lynne M. Bird, Jennifer Friedman, Virginia Clowes, Shelagh Joss, Laura Pölsler, Philippe M. Campeau, Maria Blazo, Emilia K. Bijlsma, Jill A. Rosenfeld, Christian Beetz, Zöe Powis, Kirsty McWalter, Tracy Brandt, Erin Torti, Mikaël Mathot, Shekeeb S. Mohammad, Ruth Armstrong, Vera M. Kalscheuer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Growth and Development, Pediatrics, Centre for Medical Genetics, Brussels Heritage Lab, and Medical Genetics

Subjects
Male, DISRUPTION, Chloride Channels/genetics, EXCHANGER, Mutation, Missense, LYSOSOMAL STORAGE DISEASE, VARIANTS, Neurodevelopmental Disorders/genetics, PHENOTYPE, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, Genes, X-Linked, CLC CHLORIDE, Medicine and Health Sciences, Humans, Molecular Biology, MUTATION, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHANNELS, LINKED MENTAL-RETARDATION, ASSOCIATION, GENE, Psychiatry and Mental health, Chemistry, Female, Human medicine
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

8. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Author

Sayaka Kayumi, Luis A. Pérez-Jurado, María Palomares, Sneha Rangu, Sarah E. Sheppard, Wendy K. Chung, Michael C. Kruer, Mira Kharbanda, David J. Amor, George McGillivray, Julie S. Cohen, Sixto García-Miñaúr, Clare L. van Eyk, Kelly Harper, Lachlan A. Jolly, Dani L. Webber, Christopher P. Barnett, Fernando Santos-Simarro, Marta Pacio-Míguez, Angela del Pozo, Somayeh Bakhtiari, Matthew Deardorff, Holly A. Dubbs, Kosuke Izumi, Katheryn Grand, Christopher Gray, Paul R. Mark, Elizabeth J. Bhoj, Dong Li, Xilma R. Ortiz-Gonzalez, Beth Keena, Elaine H. Zackai, Ethan M. Goldberg, Guiomar Perez de Nanclares, Arrate Pereda, Isabel Llano-Rivas, Ignacio Arroyo, María Ángeles Fernández-Cuesta, Christel Thauvin-Robinet, Laurence Faivre, Aurore Garde, Benoit Mazel, Ange-Line Bruel, Michael L. Tress, Eva Brilstra, Amena Smith Fine, Kylie E. Crompton, Alexander P.A. Stegmann, Margje Sinnema, Servi C.J. Stevens, Joost Nicolai, Gaetan Lesca, Laurence Lion-François, Damien Haye, Nicolas Chatron, Amelie Piton, Mathilde Nizon, Benjamin Cogne, Siddharth Srivastava, Jennifer Bassetti, Candace Muss, Karen W. Gripp, Rebecca A. Procopio, Francisca Millan, Michelle M. Morrow, Melissa Assaf, Andres Moreno-De-Luca, Shelagh Joss, Mark J. Hamilton, Marta Bertoli, Nicola Foulds, Shane McKee, Alastair H. MacLennan, Jozef Gecz, Mark A. Corbett, MUMC+: DA KG Lab Specialisten (9), MUMC+: DA KG Polikliniek (9), Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience

Subjects
Phenotype, Neurodevelopmental Disorders, Autism, Intellectual Disability, Familial exudative vitreoretinopathy, Microcephaly, Cerebral palsy, Humans, Genomics, Wnt Signaling Pathway, Genetics (clinical), Wnt beta catenin signaling pathway, beta Catenin
Abstract

PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP.METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay.RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants.CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

Published
2022

9. Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome

Author

Morad Ansari, Mihail Halachev, David Parry, Jose L. Campos, Elston N. D’Souza, Christopher Barnett, Andrew O. M. Wilkie, Angela Barnicoat, Chirag V. Patel, Elena Sukarova-Angelovska, Katta M. Girisha, Helen V. Firth, Katrina Prescott, Louise C. Wilson, Meriel McEntagart, Rosemarie Davidson, Sally Ann Lynch, Shelagh Joss, Simon T. Holden, Wayne K. Lam, Sanjay M. Sisodiya, Andrew J. Green, Gemma Poke, Nicola Whiffin, David R. FitzPatrick, and Alison Meynert

Abstract

AimsThis study assesses the diagnostic utility of whole genome sequence analysis in a well-characterised research cohort of individuals referred with a clinical suspicion of Cornelia de Lange syndrome (CdLS) in whom prior genetic testing had not identified a causative variant.MethodsShort read, whole genome sequencing was performed in 195 individuals from 105 families, 108 of whom were affected. 100/108 of the affected individuals had prior relevant genetic testing with no pathogenic variant being identified. The study group comprised 42 trios (affected individuals with both unaffected parents), 61 singletons (unrelated affected individuals) and two families with more than one affected individual.Results32/105 (30.5%) unrelated probands had likely causative coding region disrupting variants. 4 loci were identified in >1 proband; NIPBL (10), ANKRD11 (6), EP300 (3), EHMT1 (2). Single alleles were detected in the remaining genes (EBF3, KMT2A, MED13L, NLGN3, NR2F1, PHIP, PUF60, SET, SETD5, SMC1A, TBL1XR1). Possibly causative variants in non-coding regions of NIPBL were identified in four individuals. Single de novo variants were identified in five genes not previously reported to be associated with any developmental disorder: ARID3A, PIK3C3, MCM7, MIS18BP1 and WDR18.ConclusionsClustering of de novo non-coding variants implicate a single uORF and a small region in intron 21 in NIPBL regulation. Causative variants in genes encoding chromatin-associated proteins, with no defined influence on cohesin function, appear to result in CdLS-like clinical features.

Published
2022

10. Variants in GNAI1 Cause a Syndrome Associated with Variable Features including Developmental Delay, Seizures and Hypotonia

Author

Lauren Brady, Bryan E. Hainline, Konrad Platzer, Muhammad Zafar, Corinna Powell, Darcy J. Huismann, Heather C Mefford, Afnan Alhakeem, Daniel G. MacArthur, Alison M. Muir, Trevor L Hoffman, Mark A. Tarnopolsky, François Lecoquierre, Lindsay Rhodes, Tilman Polster, Susanne Axer-Schaefer, Alice Goldenberg, Katherine Sapp, Caoimhe S. McKenna, Jasper J. van der Smagt, Tara Montgomery, Eleina M. England, Brianna K. Murray, Myriam Srour, Lia Zitano, William B. Dobyns, Grace Noh, Angela F. Brady, Lindsey Sawyer, Ingrid M. Wentzensen, Holly Dubbs, Jane Juusola, Richard Caswell, Richard H. van Jaarsveld, Danielle DeMarzo, Samantha A. Schrier Vergano, Caleb Bupp, Grace E. VanNoy, Jose E. Martinez, Melanie O’Leary, Iris M de Lange, Shane McKee, Golder N. Wilson, Rhonda E. Schnur, Meira Meltzer, Vinod Varghese, Kristin G. Monaghan, Carole Brewer, Carolyn Tysoe, Jennifer F. Gardner, Ethan M. Goldberg, Shelagh Joss, Andrea Accogli, Chiara Klöckner, Andrea L. Gropman, and Pradeep C. Vasudevan

Subjects
0301 basic medicine, Developmental Disabilities, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Epilepsy, Neurodevelopmental disorder, Seizures, Intellectual Disability, Intellectual disability, Exome Sequencing, medicine, Humans, Global developmental delay, Child, Genetics (clinical), Exome sequencing, Genetics, Genetic heterogeneity, medicine.disease, Hypotonia, 030104 developmental biology, Neurodevelopmental Disorders, Autism, Muscle Hypotonia, medicine.symptom
Abstract

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and one was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

Published
2021

11. An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase

Author

Jozef Gecz, Chelsea Desbiens, Charles E. Schwartz, Katrin Õunap, Lance Wells, Shelagh Joss, Veronica M. Pravata, M. Gundogdu, Dirk Lefeber, Michaela Omelková, Daan M. F. van Aalten, Marios P. Stavridis, and Hannah M Stephen

Subjects
Glycosylation, X-linked intellectual disability, Review Article, Biology, Development, N-Acetylglucosaminyltransferases, Serine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Congenital Disorders of Glycosylation, Intellectual Disability, Intellectual disability, Genetics, medicine, Transferase, Animals, Humans, Point Mutation, Gene, Genetics (clinical), X chromosome, 030304 developmental biology, 0303 health sciences, Neurodevelopmental disorders, Genetic Diseases, X-Linked, Syndrome, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], chemistry, Congenital disorder of glycosylation, 030217 neurology & neurosurgery
Abstract

Intellectual disability (ID) is a neurodevelopmental condition that affects ~1% of the world population. In total 5−10% of ID cases are due to variants in genes located on the X chromosome. Recently, variants in OGT have been shown to co-segregate with X-linked intellectual disability (XLID) in multiple families. OGT encodes O-GlcNAc transferase (OGT), an essential enzyme that catalyses O-linked glycosylation with β-N-acetylglucosamine (O-GlcNAc) on serine/threonine residues of thousands of nuclear and cytosolic proteins. In this review, we compile the work from the last few years that clearly delineates a new syndromic form of ID, which we propose to classify as a novel Congenital Disorder of Glycosylation (OGT-CDG). We discuss potential hypotheses for the underpinning molecular mechanism(s) that provide impetus for future research studies geared towards informed interventions.

Published
2020

12. Identification and analysis of deletion breakpoints in four Mohr-Tranebj AE rg syndrome (MTS) patients

Author

Nanna Dahl Rendtorff, Helena Gásdal Karstensen, Marianne Lodahl, John Tolmie, Catherine McWilliam, Mads Bak, Niels Tommerup, Lusine Nazaryan-Petersen, Henricus Kunst, Melanie Wong, Shelagh Joss, Valerio Carelli, Lisbeth Tranebjærg, Rendtorff N.D., Karstensen H.G., Lodahl M., Tolmie J., McWilliam C., Bak M., Tommerup N., Nazaryan-Petersen L., Kunst H., Wong M., Joss S., Carelli V., Tranebjaerg L., KNO, MUMC+: MA Keel Neus Oorheelkunde (9), and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience

Subjects
Multidisciplinary, Membrane Transport Proteins, Membrane Transport Protein, Dystonia, Optic Atrophy, Deaf-Blind Disorders, Mitochondrial Precursor Protein Import Complex Protein, All institutes and research themes of the Radboud University Medical Center, Intellectual Disability, Mitochondrial Precursor Protein Import Complex Proteins, Deaf-Blind Disorder, Humans, Human, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Mohr-Tranebjærg syndrome is an X-linked syndrome characterized by sensorineural hearing impairment in childhood, followed by progressive neurodegeneration leading to a broad phenotypic spectrum. Genetically MTS is caused by pathogenic variants in the TIMM8A gene, including gene deletions and larger contiguous gene deletions. Some of the latter involve the neighboring gene BTK, resulting in agammaglobulinemia. By next‐generation mate‐pair sequencing we have mapped the chromosomal deletion breakpoints of one MTS case and three XLA-MTS cases and used breakpoint-spanning PCR to fine map the breakpoints by Sanger sequencing. Two of the XLA-MTS cases presented with large deletions (63.5 and 27.2 kb), and the junctional regions were characterized by long stretches of microhomology, indicating that the events have emerged through homologous recombination. Conversely, the MTS case exhibited a small 2 bp region of microhomology, and the regions were not characterized by extensive microhomology. The third XLA-MTS case had a more complex breakpoint, including a 59 bp inverted insertion, thus at least four breakpoints were involved in this event. In conclusion, mate-pair library generation combined with next-generation sequencing is an efficient method for breakpoint identification, also in regions characterized by repetitive elements.

Published
2022

13. Neuropsychiatric Risk in Children With Intellectual Disability of Genetic Origin: IMAGINE - The UK National Cohort Study

Author

Jeanne Wolstencroft, Francesca Wicks, Marie Erwood, ramya srinivasan, Amy Lafont, Husniye Timur, Zheng Ye, susan Walker, Frida Printzlau, Manoj Juj, Sarah Davies, Hayley Denver, Alice Watkins, Eleanor Kerry, Anna Lucock, Nasratullay Fatih, Sarah Wynn, Lisa Robertson, Jonathan Berg, Anne Lampe, Shelagh Joss, paul brennan, alison Kraus, astrid weber, Myfanwy Rawson, diana Johnson, pradeep vasudevan, rachel harrison, denise williams, Eamonn Maher, Usha Kini, Virginia Clowes, Jana Gurasashvili, sahar mansour, muriel Holder-Espinasse, Amy Watford, julia rankin, diana baralle, annie procter, Tamsin Ford, kate baker, Samuel chawners, Jeremy Hall, Marianne van den Bree, Michael Owen, IMAGINE Consortium, David Skuse, and F. Lucy Raymond

Published
2022

14. Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Author

Stuart Aitken, Helen V. Firth, Jeremy McRae, Mihail Halachev, Usha Kini, Michael J. Parker, Melissa M. Lees, Katherine Lachlan, Ajoy Sarkar, Shelagh Joss, Miranda Splitt, Shane McKee, Andrea H. Németh, Richard H. Scott, Caroline F. Wright, Joseph A. Marsh, Matthew E. Hurles, David R. FitzPatrick, T.W. Fitzgerald, S.S. Gerety, W.D. Jones, M. van Kogelenberg, D.A. King, J. McRae, K.I. Morley, V. Parthiban, S. Al-Turki, K. Ambridge, D.M. Barrett, T. Bayzetinova, S. Clayton, E.L. Coomber, S. Gribble, P. Jones, N. Krishnappa, L.E. Mason, A. Middleton, R. Miller, E. Prigmore, D. Rajan, A. Sifrim, A.R. Tivey, M. Ahmed, N. Akawi, R. Andrews, U. Anjum, H. Archer, R. Armstrong, M. Balasubramanian, R. Banerjee, D. Barelle, P. Batstone, D. Baty, C. Bennett, J. Berg, B. Bernhard, A.P. Bevan, E. Blair, M. Blyth, D. Bohanna, L. Bourdon, D. Bourn, A. Brady, E. Bragin, C. Brewer, L. Brueton, K. Brunstrom, S.J. Bumpstead, D.J. Bunyan, J. Burn, J. Burton, N. Canham, B. Castle, K. Chandler, S. Clasper, J. Clayton-Smith, T. Cole, A. Collins, M.N. Collinson, F. Connell, N. Cooper, H. Cox, L. Cresswell, G. Cross, Y. Crow, P.M. D’Alessandro, T. Dabir, R. Davidson, S. Davies, J. Dean, C. Deshpande, G. Devlin, A. Dixit, A. Dominiczak, C. Donnelly, D. Donnelly, A. Douglas, A. Duncan, J. Eason, S. Edkins, S. Ellard, P. Ellis, F. Elmslie, K. Evans, S. Everest, T. Fendick, R. Fisher, F. Flinter, N. Foulds, A. Fryer, B. Fu, C. Gardiner, L. Gaunt, N. Ghali, R. Gibbons, S.L. Gomes Pereira, J. Goodship, D. Goudie, E. Gray, P. Greene, L. Greenhalgh, L. Harrison, R. Hawkins, S. Hellens, A. Henderson, E. Hobson, S. Holden, S. Holder, G. Hollingsworth, T. Homfray, M. Humphreys, J. Hurst, S. Ingram, M. Irving, J. Jarvis, L. Jenkins, D. Johnson, D. Jones, E. Jones, D. Josifova, S. Joss, B. Kaemba, S. Kazembe, B. Kerr, U. Kini, E. Kinning, G. Kirby, C. Kirk, E. Kivuva, A. Kraus, D. Kumar, K. Lachlan, W. Lam, A. Lampe, C. Langman, M. Lees, D. Lim, G. Lowther, S.A. Lynch, A. Magee, E. Maher, S. Mansour, K. Marks, K. Martin, U. Maye, E. McCann, V. McConnell, M. McEntagart, R. McGowan, K. McKay, S. McKee, D.J. McMullan, S. McNerlan, S. Mehta, K. Metcalfe, E. Miles, S. Mohammed, T. Montgomery, D. Moore, S. Morgan, A. Morris, J. Morton, H. Mugalaasi, V. Murday, L. Nevitt, R. Newbury-Ecob, A. Norman, R. O’Shea, C. Ogilvie, S. Park, M.J. Parker, C. Patel, J. Paterson, S. Payne, J. Phipps, D.T. Pilz, D. Porteous, N. Pratt, K. Prescott, S. Price, A. Pridham, A. Proctor, H. Purnell, N. Ragge, J. Rankin, L. Raymond, D. Rice, L. Robert, E. Roberts, G. Roberts, J. Roberts, P. Roberts, A. Ross, E. Rosser, A. Saggar, S. Samant, R. Sandford, A. Sarkar, S. Schweiger, C. Scott, R. Scott, A. Selby, A. Seller, C. Sequeira, N. Shannon, S. Sharif, C. Shaw-Smith, E. Shearing, D. Shears, I. Simonic, D. Simpkin, R. Singzon, Z. Skitt, A. Smith, B. Smith, K. Smith, S. Smithson, L. Sneddon, M. Splitt, M. Squires, F. Stewart, H. Stewart, M. Suri, V. Sutton, G.J. Swaminathan, E. Sweeney, K. Tatton-Brown, C. Taylor, R. Taylor, M. Tein, I.K. Temple, J. Thomson, J. Tolmie, A. Torokwa, B. Treacy, C. Turner, P. Turnpenny, C. Tysoe, A. Vandersteen, P. Vasudevan, J. Vogt, E. Wakeling, D. Walker, J. Waters, A. Weber, D. Wellesley, M. Whiteford, S. Widaa, S. Wilcox, D. Williams, N. Williams, G. Woods, C. Wragg, M. Wright, F. Yang, M. Yau, N.P. Carter, M. Parker, H.V. Firth, D.R. FitzPatrick, C.F. Wright, J.C. Barrett, and M.E. Hurles

Subjects
Male, 0301 basic medicine, Proband, Nonsynonymous substitution, Heterozygote, phenotype, Developmental Disabilities, genotype, Dwarfism, Biology, Article, naive Bayes, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Similarity (network science), developmental disease, Exome Sequencing, Genotype, Genetics, medicine, Humans, tSNE, Exome, Genetic Predisposition to Disease, Child, Gene, Allele frequency, Genetics (clinical), Spectrin, Bayes Theorem, medicine.disease, Repressor Proteins, Developmental disorder, 030104 developmental biology, Mutation, Mutation (genetic algorithm), Female, 030217 neurology & neurosurgery
Abstract

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a “phenotype first” approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.

Published
2019

15. How to use genetic testing after sudden infant death syndrome

Author

Shelagh Joss and Lisa Jennifer Bryson

Subjects
Newborn screening, Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, Development period, business.industry, Stressor, Infant, Sudden infant death syndrome, Infant mortality, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Pediatrics, Perinatology and Child Health, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, business, Developed country, Sudden Infant Death, Genetic testing, Cause of death
Abstract

Since the early 1990s, the rate of sudden infant death syndrome (SIDS) has reduced by over 80% in the UK, principally due to public health education regarding safer sleep, in particular the ‘Back-to-Sleep’ campaign, and to a smaller degree the introduction of newborn screening for metabolic conditions.1 2 Despite this, SIDS is still one of the leading causes of postneonatal infant death in developed countries. The triple risk hypothesis states that SIDS occurs due to having (1) a vulnerable infant (2) during a critical development period and (3) a minor exogenous stressor (figure 1). Genetic testing is likely to develop a bigger role in identifying vulnerabilities in the future as research in this field progresses and testing becomes easier.3 Figure 1 The triple risk hypothesis. When an infant dies unexpectedly (SUDI), a full review of the clinical history, death scene investigation, clinical investigations (including biochemistry, toxicology, microbiology, virology and metabolic tests) and postmortem will be arranged. If no cause of death is found then the diagnosis is SIDS or unexplained SUDI (see table 1). View this table: Table 1 Definitions A small proportion of these cases may be linked to an underlying cardiac …

Published
2021

16. Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder

Author

Joshua J. Ziarek, Manju A. Kurian, Daniel Scott, Rebekah Barrick, Kate Baker, Jasper J. van der Smagt, Anna Kolesnik-Taylor, Jenny Thies, Holly Melland, Lucy Loong, Shelagh Joss, Marjolein H. Willemsen, Fabian Bumbak, Sarah L. Gordon, Abinayah John, Elise Ng-Cordell, R. Pfundt, Christina Fagerberg, Majid Alfadhel, Frances Emslie, Martin Jakob Larsen, Panayiotis Constantinou, Tjitske Kleefstra, Mathilde Nizon, and Richard Chang

Subjects
Sleep disorder, Movement disorders, business.industry, Cognition, medicine.disease, Phenotype, Genotype-phenotype distinction, Neurodevelopmental disorder, Intellectual disability, Medicine, Missense mutation, medicine.symptom, business, Neuroscience
Abstract

PurposeSynaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioural disturbance and EEG abnormalities. Here, we expand the genotypes and phenotypes and identify discriminating features of this disorder.MethodsWe describe 22 individuals with 15 de novo missense SYT1 variants. Evidence for pathogenicity is discussed, including ACMG criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioural data for 14 cases are compared to other monogenic neurodevelopmental disorders.ResultsFour variants lie in the C2A domain with the remainder in the C2B. We classify 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes include delayed developmental milestones, ophthalmic problems, abnormal EEG, movement disorders and sleep disturbance. Discriminating behavioural characteristics were severity of motor and communication impairment, presence of motor stereotypies and mood instability.ConclusionSYT1 variants associated with neurodevelopmental disorder extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severity than initially reported. This work guides diagnosis and molecular understanding of this rare neurodevelopmental disorder, and highlights a key role for SYT1 function in emotional regulation, motor control and emergent cognitive function.

Published
2021

17. The phenotype of Sotos syndrome in adulthood: A review of 44 individuals

Author

Nayana Lahiri, Katrina Tatton-Brown, Edward Blair, Trevor Cole, Julie Vogt, Emma McCann, Sally Ann Lynch, Anna Zachariou, Shelagh Joss, Jenny Morton, Tazeen Ashraf, Deborah J. Shears, Sahar Mansour, Elizabeth Thompson, Nicole Motton, Alex Henderson, Chey Loveday, Blanca Gener, Katie Riches, Melita Irving, Huw Dorkins, Alan Fryer, Jill Clayton-Smith, David Goudie, Alexandra Murray, Zornitza Stark, Vaughan Keeley, Alison Foster, and Michael Wright

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Hearing loss, Scoliosis, Intellectual Disability, Intellectual disability, Genetics, Humans, Medicine, Child, Genetics (clinical), Muscle contracture, Sotos Syndrome, business.industry, Sotos syndrome, Macrocephaly, Facies, Tall Stature, medicine.disease, Phenotype, Lymphedema, Female, medicine.symptom, business
Abstract

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.

Published
2019

18. Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

Author

Veronica M. Pravata, Villo Muha, Mehmet Gundogdu, Andrew T. Ferenbach, Poonam S. Kakade, Vasudha Vandadi, Ariane C. Wilmes, Vladimir S. Borodkin, Shelagh Joss, Marios P. Stavridis, and Daan M. F. van Aalten

Subjects
Neurogenesis, N-Acetylglucosaminyltransferases, Biochemistry, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Loss of Function Mutation, Catalytic Domain, Animals, Humans, Point Mutation, 030304 developmental biology, 0303 health sciences, Multidisciplinary, neurodevelopment, Genetic Diseases, X-Linked, Twins, Monozygotic, Biological Sciences, PNAS Plus, intellectual disability, O-GlcNAc, Drosophila, Female, Host Cell Factor C1, 030217 neurology & neurosurgery
Abstract

Significance Protein O-GlcNAcylation is a posttranslational modification essential for development. Recently, mutations in the O-GlcNAc transferase (OGT) substrate binding domain have been described that lead to intellectual disability, but the mechanisms underpinning pathogenesis remain to be explored. This work describes the first point mutation in the OGT catalytic domain leading to effects on O-GlcNAcylation and Host cell factor 1 processing in vitro and in a stem cell/Drosophila model, resulting in delayed neuronal differentiation. This establishes a potential link between OGT activity and intellectual disability., O-GlcNAc transferase (OGT) is an X-linked gene product that is essential for normal development of the vertebrate embryo. It catalyses the O-GlcNAc posttranslational modification of nucleocytoplasmic proteins and proteolytic maturation of the transcriptional coregulator Host cell factor 1 (HCF1). Recent studies have suggested that conservative missense mutations distal to the OGT catalytic domain lead to X-linked intellectual disability in boys, but it is not clear if this is through changes in the O-GlcNAc proteome, loss of protein–protein interactions, or misprocessing of HCF1. Here, we report an OGT catalytic domain missense mutation in monozygotic female twins (c. X:70779215 T > A, p. N567K) with intellectual disability that allows dissection of these effects. The patients show limited IQ with developmental delay and skewed X-inactivation. Molecular analyses revealed decreased OGT stability and disruption of the substrate binding site, resulting in loss of catalytic activity. Editing this mutation into the Drosophila genome results in global changes in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads to loss of O-GlcNAcase and delayed differentiation down the neuronal lineage. These data imply that catalytic deficiency of OGT could contribute to X-linked intellectual disability.

Published
2019

19. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author

Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], 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), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and 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 )

Subjects
CHROMATIN, Male, 0301 basic medicine, Autism, Sequence Homology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, 0302 clinical medicine, SCHIZOPHRENIA, Gene expression, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, de novo variants, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, biology, neurodevelopmental disorders, histone acetylation, Adaptor Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Biological Sciences, Prognosis, Phenotype, Chromatin, Mental Health, Histone, intellectual disability, Child, Preschool, Female, REGULATOR, congenital malformations, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], BRAIN-DEVELOPMENT, Adult, Adolescent, Histone acetyltransferase complex, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Deciphering Developmental Disorders study, autism spectrum disorder, KAT6B, RNAI SCREEN, Young Adult, 03 medical and health sciences, CAUSES Study, Rare Diseases, Intellectual Disability, Report, COFACTOR, medicine, RUBINSTEIN-TAYBI-SYNDROME, Humans, Amino Acid Sequence, Autistic Disorder, Preschool, Gene, Genetic Association Studies, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Signal Transducing, Neurosciences, Infant, medicine.disease, TRRAP, Brain Disorders, SELF-RENEWAL, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, biology.protein, Missense, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Published
2019

20. Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants

Author

Julian C. Knight, Elma Stephen, Houman Ashrafian, Andreas Brunklaus, Ioana Cutcutache, Shelagh Joss, Alice Jollands, Liam Dorris, Martin Armstrong, Elizabeth Pilley, Jay Shetty, Joseph D. Symonds, Katherine S. Elliott, Kirsty Stewart, Daniela T. Pilz, Mary O'Regan, Sarah L. Gardiner, Martin Kirkpatrick, Sameer M. Zuberi, Matthew Page, S. MacLeod, Louise A Diver, and Ailsa McLellan

Subjects
Male, Drug Resistant Epilepsy, medicine.medical_specialty, Pediatrics, Cohort Studies, Epilepsy, Epidemiology, medicine, Humans, genetics, Prospective Studies, Global developmental delay, Retrospective Studies, AcademicSubjects/SCI01870, business.industry, Incidence (epidemiology), Infant, Newborn, Infant, Original Articles, Odds ratio, medicine.disease, Comorbidity, Causality, Scotland, Socioeconomic Factors, Child, Preschool, Epilepsy syndromes, incidence, Etiology, epilepsy, Female, AcademicSubjects/MED00310, epidemiology, precision, Neurology (clinical), business, Follow-Up Studies
Abstract

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216–263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251–357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139–233), χ2 odds ratio = 1.7 (95% CI 1.3–2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations., In a prospective study involving all children presenting with epilepsy aged under 3 years in Scotland, Symonds et al. show that epilepsies of undetermined aetiology present more frequently in socially disadvantaged groups. Aetiology is the strongest predictor of outcome, and genetic testing should be prioritized.

Published
2021

21. SCN3A ‐related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation

Author

Thuy Anh Vu, Sally Ackermann, Andrew E. Fry, Seok Kyu Kang, Shelagh Joss, Katrien Stouffs, Satoko Miyatake, Katherine A. Fawcett, Ethan M. Goldberg, Elena Parrini, Natalie Hauser, Anna E. Jansen, Daniela T. Pilz, Daphna Marom, Adeline Jacquinet, Katherine L. Helbig, Yuh Fujiwara, Natalie Lippa, Orit Reish, Ingo Helbig, Bruria Ben-Zeev, Shraddha Srinivasan, Pradeep Vasudevan, Renzo Guerrini, Careni Spencer, Lieve Verstraete, Agnieszka Charzewska, Christopher H. Thompson, Jérôme Clatot, Jennifer A. Kearney, David R. FitzPatrick, Haim Bassan, Victoria Harrison, Naomichi Matsumoto, Tariq Zaman, Dorota Hoffman-Zacharska, Clinical sciences, Medical Genetics, Reproduction and Genetics, Physiotherapy, Human Physiology and Anatomy, Pediatrics, Public Health Sciences, Mental Health and Wellbeing research group, and Neurogenetics

Subjects
0301 basic medicine, Adult, Male, Adolescent, Biology, Sodium Channels, Article, 03 medical and health sciences, Epilepsy, SCN3A, 0302 clinical medicine, Neurodevelopmental disorder, Fetus, Channelopathy, Intellectual disability, medicine, NAV1.3 Voltage-Gated Sodium Channel, Missense mutation, Humans, Child, Sodium channel, Brain, Genetic Variation, Infant, medicine.disease, Electrophysiology, 030104 developmental biology, HEK293 Cells, Neurology, Neurodevelopmental Disorders, Child, Preschool, Female, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery
Abstract

Objective\ud \ud Pathogenic variants in SCN3A , encoding the voltage‐gated sodium channel subunit Nav1.3, cause severe childhood‐onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A ‐related neurodevelopmental disorder.\ud Methods\ud \ud Patients were ascertained via an international collaborative network. We compared sodium channels containing wild‐type vs. variant Nav1.3 subunits co‐expressed with β1 and β2 subunits using whole‐cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK‐293 T cells).\ud Results\ud \ud Of 22 patients with pathogenic SCN3A variants, most had treatment‐resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20; 75%). Many, but not all (15/19; 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4–6 of domains II‐IV. Most pathogenic missense variants tested (10/11; 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.\ud Interpretation\ud \ud Our study defines SCN3A‐ related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in over 75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis.

Published
2020

22. A new 1p36.13-1p36.12 microdeletion syndrome characterized by learning disability, behavioral abnormalities, and ptosis

Author

Shelagh Joss, Farah Kanani, Charlotte Brasch-Andersen, Line Aagaard Nolting, Michael J. Parker, Maria Lisa Dentici, Joan P. Jørgensen, Helen Cox, Sara Loddo, Christina Fagerberg, Antonio Novelli, and Andrew E. Fry

Subjects
0301 basic medicine, Male, chromosomes, Candidate gene, Developmental Disabilities, Ubiquitin-Protein Ligases, Chromosome Disorders, pair 1, 030105 genetics & heredity, 03 medical and health sciences, Ptosis, Intellectual Disability, Intellectual disability, ptosis, Genetics, medicine, Blepharoptosis, Humans, human, Gene, Genetics (clinical), Genetic Association Studies, CapZ Actin Capping Protein, learning disability, 1p36 deletion syndrome, business.industry, Learning Disabilities, chromosome deletion, Microdeletion syndrome, medicine.disease, 030104 developmental biology, Phenotype, Chromosomes, Human, Pair 1, Learning disability, Speech delay, Calmodulin-Binding Proteins, Female, medicine.symptom, Chromosome Deletion, business, behavioral abnormality
Abstract

Two 1p36 contiguous gene deletion syndromes are known so far: the terminal 1p36 deletion syndrome and a 1p36 deletion syndrome with a critical region located more proximal at 1p36.23-1p36.22. We present even more proximally located overlapping deletions from seven individuals, with the smallest region of overlap comprising 1 Mb at 1p36.13-1p36.12 (chr1:19077793-20081292 (GRCh37/hg19)) defining a new contiguous gene deletion syndrome. The characteristic features of this new syndrome are learning disability or mild intellectual disability, speech delay, behavioral abnormalities, and ptosis. The genes UBR4 and CAPZB are considered the most likely candidate genes for the features of this new syndrome.

Published
2020

23. MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis

Author

Géraldine Viot, Sara Halbach, Sandra Yang, William T. Gibson, Megan T. Cho, Sabine Luettgen, Pierre-Marie Martin, Karen W. Gripp, Christopher T. Gordon, Michael J. Bamshad, Jonas Denecke, Benjamin Apple, Thierry Bienvenu, William B. Dobyns, Elizabeth Francisco, Jill R. Murrell, Deborah A. Nickerson, Nadja Ehmke, Angela E. Lin, Kelly Radtke, Lisenka E.L.M. Vissers, Shelagh Joss, Farah R. Zahir, Louise Amlie-Wolf, Francisca Millan, Joan M. Stoler, Michael Parker, Youngha Lee, Carey McDougall, Denise Horn, Ruth McGowan, Elaine H. Zackai, Nicolas Lebrun, Ingrid M. Wentzensen, Zöe Powis, Oliver Puk, Nancy Vegas, Dan Doherty, Noa Lev-El, Amanda Barone Pritchard, Joseph T. Shieh, Francesca Filippini, Mariëtte J.V. Hoffer, Russell R. Reid, Valérie Cormier-Daire, Murim Choi, Michele G. Mehaffey, Stanislas Lyonnet, Jan M. Friedman, Sarina G. Kant, Yuri A. Zarate, David Viskochil, Gordon K.C. Leung, Angela M. Kaindl, Steven L.C. Pei, Christopher C.Y. Mak, Clémantine Dimartino, Koenraad Devriendt, Tiong Yang Tan, Mullin H.C. Yu, Chumei Li, Brian H.Y. Chung, Tim M. Strom, Lindsay B. Henderson, Elliot S. Stolerman, Trevor L Hoffman, Lina Basel-Salmon, Davor Lessel, Chelsea Roadhouse, Gisele E. Ishak, Caitlin Troyer, Jong-Hee Chae, Claudia Gonzaga-Jauregui, Ann Seman, Naama Orenstein, Marcie A. Steeves, Eric G. Bend, James D. Weisfeld-Adams, Jamel Chelly, William G. Wilson, Jeanne Amiel, and Darrel Waggoner

Subjects
0301 basic medicine, Proband, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, Intellectual disability, medicine, Craniofacial, Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MN1, rhombencephalosynapsis, Original Articles, Perisylvian polymicrogyria, medicine.disease, craniofacial development, MCTT syndrome, 030104 developmental biology, medicine.anatomical_structure, intellectual disability, Cerebellar vermis, Trigeminal artery, Neurology (clinical), Haploinsufficiency, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 218289.pdf (Publisher’s version ) (Closed access) MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

Published
2020

24. The broad phenotypic spectrum of PPP2R1A -related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Author

Amy McTague, Siddharth Srivastava, Tamison Jewett, Ali Al-Beshri, Constance Smith-Hicks, Shelagh Joss, Jennifer A. Sullivan, Sarju G. Mehta, Koenraad Devriendt, Pascal Joset, Laurence Faivre, Emma Kivuva, William G. Wilson, Gunnar Houge, Naama Orenstein, Yana Hoorne, Vickie L. Hannig, Malou Heijligers, Bart Loeys, Vandana Shashi, Katrina Prescott, Iris Verbinnen, Annick Toutain, Lauren M. Baldwin, Stephen P. Fulton, Katharina Steindl, Anne Marie Childs, Anna Chassevent, Shelley Towner, Cornelia Daumer-Haas, Oded Wechsberg, Alison Male, Hannah F. Johnson, Wendy K. Chung, Anita Rauch, Anna Ruiz, Isabelle Maystadt, Sara Reynhout, Sébastien Moutton, Yvette van Ierland, Veerle Janssens, Frédéric Laumonnier, Martina Baethmann, Lisa Lenaerts, Vani Jain, Vinod Varghese, Suzanne M. Koudijs, Elisabeth Gabau, Frédérique Bonnet-Brilhault, Rizwan Hamid, Susan E. Holder, Barbara Plecko, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Queen Elizabeth University Hospital (Glasgow), Kennedy Krieger Institute [Baltimore], University of Antwerp (UA), Universität Zürich [Zürich] = University of Zurich (UZH), Addenbrooke’s Hospital [Cambridge, UK], Columbia University Medical Center (CUMC), Columbia University [New York], North West Thames Regional Genetics Service [London, UK] (Harrow), North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow-Northwick Park Hospital [Harrow, UK] (NPH), Wake Forest University, University of Virginia [Charlottesville], Boston Children's Hospital, Prenatal Medicine Munich [Munich, Germany] (PMM), Klinikum Dritter Orden [Munich], Universitat Autònoma de Barcelona (UAB), University Hospital of Wales [Cardiff, UK], University of Alabama at Birmingham [ Birmingham] (UAB), Le Bonheur Children's Hospital [Memphis, TN, USA] (LBCH), Schneider Children’s Medical Center of Israel [Petah Tikva], Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Leeds Teaching Hospitals NHS Trust, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Maison de Santé Protestante de Bordeaux-Bagatelle (MSPB), Duke University Medical Center, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Royal Devon and Exeter NHS Foundation Trust [UK], Great Ormond Street Institute of Child Health [London, UK] (UCL), University College of London [London] (UCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Medical University Graz, Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Haukeland University Hospital, University of Bergen (UiB), Leuven Brain Institute [Leuven, Belgium] (LBI), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Clinical Genetics, University of Virginia, University Hospital of Wales (UHW), Tel Aviv University (TAU), Great Ormond Street Institute of Child Health (UCL), and Laumonnier, Frédéric

Subjects
0301 basic medicine, Microcephaly, [SDV]Life Sciences [q-bio], Intellectual disability, 030105 genetics & heredity, Bioinformatics, Epilepsy, Neurodevelopmental disorder, CORE, Protein Phosphatase 2, SPECIFICITY, Genetics (clinical), PROTEIN PHOSPHATASE 2A, Phenotype, Hypotonia, FAMILY, 3. Good health, PP2A, [SDV] Life Sciences [q-bio], PPP2R1A, PPP2R5D, INSIGHTS, intellectual disability, Muscle Hypotonia, medicine.symptom, Language delay, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, business.industry, Macrocephaly, DEPHOSPHORYLATION, medicine.disease, neurodevelopmental disorder, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, SUBUNIT, epilepsy, Human medicine, TAU, business, Transcription Factors
Abstract

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported. ispartof: Genetics In Medicine vol:23 issue:2 ispartof: location:United States status: Published online

Published
2020

25. De novo variants in CNOT3 cause a variable neurodevelopmental disorder

Author

A. van Haeringen, Laurence Faivre, S Tomkins, Amélie Piton, Shelagh Joss, Emmelien Aten, C I de Bie, Ruth Newbury-Ecob, Emma Kivuva, R Ibitoye, Els A. J. Peeters, Miranda Splitt, Bronwyn Kerr, F Tranmauthem, Nicola Foulds, Andrew Collins, J Kennedy, David Geneviève, Marije Koopmans, Richard Martin, Sarah F. Smithson, Nolwenn Jean-Marçais, Jacques C. Giltay, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Leiden University Medical Center (LUMC), University of Southampton, University Medical Center [Utrecht], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University of Glasgow, University Hospitals Bristol, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], University of Exeter Medical School, University of Exeter, Unité de Biotechnologie, Biocatalyse et Biorégulation (U3B), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), St. Michael's Hospital, Haga Teaching Hospital [Hague], University of Bristol [Bristol], Laboratoire de Diagnostic Génétique [CHU Strasbourg], and Université de Strasbourg (UNISTRA)-CHU Strasbourg

Subjects
Male, Proband, Developmental Disabilities, Developmental disorder, Mutation, Missense, Novo variants in CNOT3, Hypotonia, Haploinsufficiency, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual Disability, Exome Sequencing, Genetics, medicine, Humans, Learning, Missense mutation, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, Genetic Association Studies, Genetics (clinical), Exome sequencing, Behavior, 0303 health sciences, 030305 genetics & heredity, Genetic Variation, medicine.disease, United Kingdom, Musculoskeletal Abnormalities, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Muscle Hypotonia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Ireland, Sequence Alignment, Transcription Factors
Abstract

International audience; As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.

Published
2019

26. Heterozygous truncation mutations of theSMC1Agene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases

Author

AK Lampe, Jamie Cruden, Peter D. Turnpenny, Joseph D. Symonds, J. S. Tan, Anita M. Devlin, Shelagh Joss, Suresh Somarathi, Tara Montgomery, Melissa Lees, Jelena Pozojevic, Ailsa McLellan, Nataliya DiDonato, Vivek Mundada, Lesley Nairn, Alan Donaldson, Ajoy Sarkar, Jens Schallner, David R. FitzPatrick, Frank J. Kaiser, Kay Metcalfe, William P Whitehouse, Ilaria Parenti, and Sameer M. Zuberi

Subjects
Male, 0301 basic medicine, Heterozygote, Cornelia de Lange Syndrome, Cohesin complex, Chromosomal Proteins, Non-Histone, Cell Cycle Proteins, Biology, SMC1A, medicine.disease_cause, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Seizures, Journal Article, medicine, Humans, Missense mutation, Child, X chromosome, Genetics, Mutation, Electroencephalography, medicine.disease, 030104 developmental biology, Neurology, Child, Preschool, Female, Neurology (clinical), Developmental regression, 030217 neurology & neurosurgery
Abstract

Objective:\ud \ud The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation.\ud Method:\ud \ud Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained.\ud Results:\ud \ud Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between

Published
2017

27. Incidence and phenotypes of childhood-onset genetic epilepsies:a prospective population-based national cohort

Author

Alice Jollands, Elma Stephen, Louise A Diver, Ailsa McLellan, Margaret Wilson, Mary Callaghan, Sarah L. Gardiner, Lesley Nairn, Andreas Brunklaus, Jamie Andrew, Calum A. Morrison, Jane MacDonnell, Rosemary Grattan, Martin Kirkpatrick, Shelagh Joss, Jean McKnight, Daniela T. Pilz, Bethan Lang, Jay Shetty, Sameer M. Zuberi, Philip Brink, Angela Vincent, Christine Findlay, Liam Dorris, Meghan M Slean, Mary O'Regan, Joseph D. Symonds, Jamie Cruden, S. MacLeod, Kirsty Stewart, Alan Webb, and Ishaq Abu-Arafeh

Subjects
Adult, 0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Population, Cohort Studies, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Humans, genetics, Prospective Studies, Child, education, Letters to the Editor, Genetic testing, education.field_of_study, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Incidence, Infant, Newborn, Infant, Original Articles, medicine.disease, Comorbidity, humanities, Confidence interval, 030104 developmental biology, Phenotype, Scotland, Child, Preschool, Cohort, epidemiology, precision, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Cohort study
Abstract

See Scheffer (doi:10.1093/brain/awz208) for a scientific commentary on this article. In a prospective population-based cohort study, Symonds et al. perform high-throughput genetic testing in children presenting with seizures before 3 years of age, and provide incidence estimates for the most common single-gene epilepsies. One quarter of cases are found to have a genetic cause, and 80% of the genetic diagnoses are found to have potential treatment implications., Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

Published
2019

28. 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 George’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

29. G150 Aetiological investigations and treatment outcomes in a prospective population-based cohort of children with epilepsy <3 years

Author

Andreas Brunklaus, Katherine S. Elliott, Shelagh Joss, Julian C. Knight, Joseph D. Symonds, D.T. Pilz, Sameer M. Zuberi, and S. MacLeod

Subjects
Pediatrics, medicine.medical_specialty, education.field_of_study, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Population, medicine.disease, Epilepsy, Gene duplication, Cohort, medicine, Etiology, business, education, Trisomy, Genetic testing
Abstract

Objectives To report the yield from all aetiological investigations in a prospective population–based cohort of children presenting with new–onset epilepsy To calculate the impact of gene panel testing on diagnostic yield To calculate the impact of Whole Genome Sequencing (WGS) on diagnostic yield in drug–resistant epilepsy (DRE) cases Methods Early-onset epilepsy cases ( Capture-recapture analysis was used to estimate missing cases. Follow-up was for minimum 12 months. Presence or absence of DRE and global development delay (GDD) at latest follow-up was recorded for each case. All cases without identified aetiology after neuroimaging and targeted genetic/metabolic tests were tested on a 104 gene epilepsy panel. Those with DRE who were negative on gene panel testing underwent WGS. Results Population statistics for the region were: Total population (2017) 3.00 million; mean births per year (2011–2016) 31 000. 229 patients were identified. Using capture-recapture the estimated total was 236. The estimated incidence of epilepsy At latest follow-up 83 (36%) had DRE and 112 (49%) had GDD. 75 (33%) patients had aetiology identified prior to gene panel testing. Of these 37 (49%) were structural, 32 (43%) genetic (6 trisomy, 18 microdeletion/duplication, 8 single gene disorder), 4 (5%) metabolic, 1 immune, and 1 infectious. A further 42 (18%) had a diagnosis made through gene panel testing, increasing overall diagnostic yield to 51%. Of the 83 DRE patients, 41 (49%) had an aetiological diagnosis prior to gene panel testing. A further 21 had a diagnosis through gene panel testing (cumulative yield=75%) and another 9 had a diagnosis through WGS (86%). Conclusion One in 400 children develops epilepsy before their third birthday. One third develop drug resistance and half have GDD. With extensive genetic testing >85% of children with DRE have a cause identified.

Published
2019

30. KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants

Author

Bruce Hopper, Ellen Macnamara, Valerie A. Arboleda, David Goudie, Nobuhiko Okamoto, Anne Blomhoff, Elizabeth M. McCormick, Joanna Kennedy, Zornitza Stark, Usha Kini, Benjamin Cogné, Susan Schelley, Emilie D. Douine, Stanley F. Nelson, Tiong Yang Tan, Mark Williams, Shelagh Joss, Kimberley Bradbury, Helen Heussler, Hakon Hakonarson, Claudia A. L. Ruivenkamp, Dusica Babovic-Vuksanovic, Jennifer L. Murphy, Esther A. R. Nibbeling, Ruth Armstrong, Mohamed Wafik, Melissa Lees, Louanne Hudgins, Mariet W. Elting, Naomichi Matsumoto, Ruth Newbury-Ecob, Benjamin Kamien, Sarina G. Kant, Alexander J. M. Dingemans, Eric W. Klee, Edward Blair, Bertrand Isidor, Dong Li, Victoria McKay, Marni J. Falk, Margot R.F. Reijnders, Patrick R. Blackburn, Patrick Yap, Phillis Lakeman, Kate Chandler, Janneke H M Schuurs-Hoeijmakers, Celia Duff-Farrier, Andrew Green, Ingrid Scurr, Noriko Miyake, Chirag Patel, Erasmus MC other, Pediatrics, Human Genetics, Human genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Adult, Male, KAT6A syndrome, Microcephaly, Adolescent, Genotype, Developmental Disabilities, Biology, Article, 03 medical and health sciences, Exon, Young Adult, genetic diagnosis, 0302 clinical medicine, Intellectual disability, chromatin modifiers, medicine, Missense mutation, Humans, Protein Isoforms, Exome, Child, Genetics (clinical), Genetic Association Studies, Histone Acetyltransferases, Genetics, Infant, medicine.disease, Phenotype, Penetrance, 030104 developmental biology, intellectual disability, Child, Preschool, Speech delay, Mutation, Female, medicine.symptom, Chromosome Deletion, 030217 neurology & neurosurgery, phenotypic spectrum
Abstract

Purpose: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. Methods: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. Results: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype– phenotype correlations show that late-truncating pathogenic variants (exons 16–17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. Conclusion: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

Published
2019

31. Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

Author

Merryn V. E. Macville, David Hunt, Richard Webster, Suzanna G.M. Frints, Alberto Fernández-Jaén, Shelagh Joss, Andrew G. L. Douglas, Margje Sinnema, Lesley M McGregor, Vera M. Kalscheuer, Abhijit Dixit, Paulien A. Terhal, Arthur Lee, Sébastien Jacquemont, Omar A. Abdul-Rahman, Peter Wieacker, Koen L.I. van Gassen, Norbert Utzig, Marcus Lee, Vanessa Suckow, Gunnar Houge, Danita Velasco, Cheryl Longman, Holly H. Zimmerman, Elizabeth C. Engle, Bryce A. Mendelsohn, Salwan Al-Nasiry, Suzanne M. Koudijs, Saskia M. Maas, Diana Baralle, Hiromi Hirata, Kees E. P. van Roozendaal, Servi J. C. Stevens, Raoul C.M. Hennekam, Roberto Colombo, Ulrike Kordaß, Gyri Aasland Gradek, Friederike Hennig, APH - Quality of Care, Human Genetics, Amsterdam Neuroscience - Complex Trait Genetics, MUMC+: DA KG Bedrijfsbureau (9), Klinische Genetica, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), Obstetrie & Gynaecologie, MUMC+: MA Medische Staf Obstetrie Gynaecologie (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: MA Med Staf Spec Neurologie (9)

Subjects
Male, INTELLECTUAL DISABILITY, Enfermedad del sistema nervioso, CONTRACTURES, Pie zambo, Genes, X-Linked, Missense mutation, Genetics(clinical), Frameshift Mutation, EXCHANGE, Zebrafish, Genetics (clinical), Sequence Deletion, media_common, Arthrogryposis, Genetics, Sex Characteristics, Paraplejía, medicine.diagnostic_test, 2 microdeletion, Intracellular Signaling Peptides and Proteins, complicated spastic paraplegia/ spasticity, METHYLATION, Espasticidad muscular, Nuclear Proteins, spasticity, Phenotype, Pedigree, Codon, Nonsense, akinesia, Female, Neurogenic arthrogryposis multiplex congenita, media_common.quotation_subject, fetal hypo, Nonsense, Mutation, Missense, Biology, DIAGNOSIS, Article, Frameshift mutation, medicine, Animals, Humans, Genetic Predisposition to Disease, Gene, Genetic testing, ZC4H2-Associated Rare Disorders (ZARD), SPECTRUM, Arthrogryposis multiplex congenita, MUTATIONS, fetal hypo-/akinesia, feet, club foot/-feet, ZC4H2, GENE, Genética, DELETIONS, Disease Models, Animal, complicated spastic paraplegia, Mutation, Xq11.2 microdeletion, Xq11, MENTAL-RETARDATION, club foot
Abstract

Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC. Sin financiación 4.124 JCR (2019) Q1, 45/178 Genetics & Heredity 2.410 SJR (2019) Q1, 43/356 Genetics No data IDR 2019 UEM

Published
2019

32. 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

33. Correction: KAT6A Syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants

Author

Tatjana Bierhals, Patrick Yap, Phillis Lakeman, Esther A. R. Nibbeling, Claudia A. L. Ruivenkamp, Stanley F. Nelson, Anne Blomhoff, Shelagh Joss, Celia Duff-Farrier, Ruth Armstrong, Jessika Johannsen, Noriko Miyake, Chirag Patel, Melissa Lees, Dong Li, Kate Chandler, Elizabeth M. McCormick, Mohamed Wafik, Davor Lessel, Ruth Newbury-Ecob, Zornitza Stark, Helen Heussler, Nobuhiko Okamoto, Benjamin Kamien, Kimberley Bradbury, Bertrand Isidor, Hakon Hakonarson, Maja Hempel, Andrew Green, Mariet W. Elting, Alexander J. M. Dingemans, Ellen Macnamara, Bruce Hopper, Naomichi Matsumoto, Edward Blair, Jennifer L. Murphy, Benjamin Cogné, Joanna Kennedy, Valerie A. Arboleda, Usha Kini, Janneke H M Schuurs-Hoeijmakers, David Goudie, Emilie D. Douine, Dusica Babovic-Vuksanovic, Eric W. Klee, Sarina G. Kant, Susan Schelley, Marni J. Falk, Margot R.F. Reijnders, Patrick R. Blackburn, Ingrid Scurr, Victoria McKay, Tiong Yang Tan, Mark Williams, and Louanne Hudgins

Subjects
Correlation, Genetics, MEDLINE, Biology, Genetics (clinical), Genotype phenotype
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

34. Rubinstein–Taybi syndrome type 2: report of nine new cases that extend the phenotypic and genotypic spectrum

Author

Shu Yau, Mohnish Suri, S. Lillis, Shelagh Joss, Muriel Holder-Espinasse, Emma Hobson, Jane A. Hurst, Emma Clement, William Reardon, Moira Blyth, Maryam Al-Shehhi, Sally Ann Lynch, Mark J. Hamilton, and Ruth Newbury-Ecob

Subjects
Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Microcephaly, Adolescent, Genotype, 030105 genetics & heredity, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual disability, medicine, Humans, Amino Acid Sequence, Syndactyly, Craniofacial, Child, Genetic Association Studies, Genetics (clinical), Exome sequencing, Rubinstein-Taybi Syndrome, Genetics, Rubinstein–Taybi syndrome, business.industry, Facies, Sequence Analysis, DNA, General Medicine, medicine.disease, CREB-Binding Protein, Phenotype, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, Female, Anatomy, business, Haploinsufficiency, E1A-Associated p300 Protein
Abstract

Rubinstein-Taybi syndrome (RTS) is an autosomal dominant neurodevelopmental disorder characterized by growth deficiency, broad thumbs and great toes, intellectual disability and characteristic craniofacial appearance. Mutations in CREBBP account for around 55% of cases, with a further 8% attributed to the paralogous gene EP300. Comparatively few reports exist describing the phenotype of Rubinstein-Taybi because of EP300 mutations. Clinical and genetic data were obtained from nine patients from the UK and Ireland with pathogenic EP300 mutations, identified either by targeted testing or by exome sequencing. All patients had mild or moderate intellectual impairment. Behavioural or social difficulties were noted in eight patients, including three with autistic spectrum disorders. Typical dysmorphic features of Rubinstein-Taybi were only variably present. Additional observations include maternal pre-eclampsia (2/9), syndactyly (3/9), feeding or swallowing issues (3/9), delayed bone age (2/9) and scoliosis (2/9). Six patients had truncating mutations in EP300, with pathogenic missense mutations identified in the remaining three. The findings support previous observations that microcephaly, maternal pre-eclampsia, mild growth restriction and a mild to moderate intellectual disability are key pointers to the diagnosis of EP300-related RTS. Variability in the presence of typical facial features of Rubinstein-Taybi further highlights clinical heterogeneity, particularly among patients identified by exome sequencing. Features that overlap with Floating-Harbor syndrome, including craniofacial dysmorphism and delayed osseous maturation, were observed in three patients. Previous reports have only described mutations predicted to cause haploinsufficiency of EP300, whereas this cohort includes the first described pathogenic missense mutations in EP300.

Published
2016

35. De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females

Author

Pawel Stankiewicz, Claude Moraine, Astrid Grimme, Martine Raynaud, Jillian Nicholl, D. Hamlin, Mauricio R. Delgado, Linda Manwaring, H Van Bokhoven, Zhiyv Niu, Stefanie Weinert, J. Wynn, Jozef Gecz, Thomas J. Jentsch, Vanessa Suckow, Vera M. Kalscheuer, Hossein Najmabadi, Jackie Boyle, A. Sommer, Maureen Holvoet, J. M. Goehringer, Eric Haan, M. P. Pietryga, Luis Rohena, John Tolmie, Luciana Musante, Utz Fischer, Floor A. M. Duijkers, Wendy K. Chung, Friederike Hennig, Jan Maarten Cobben, Elizabeth E. Palmer, Tjitske Kleefstra, H Van Esch, B. M. Faux, Michael Field, Kimia Kahrizi, Deepa Sirsi, Melanie Leffler, T. Stuhlmann, Dorothy K. Grange, Jill A. Rosenfeld, Hans-Hilger Ropers, S. P. Lodh, Marie Shaw, Sailaja Golla, E. Bernardo, Shelagh Joss, Thomas D. Challman, General Paediatrics, ANS - Cellular & Molecular Mechanisms, Paediatric Genetics, Other Research, and Human Genetics

Subjects
Male, 0301 basic medicine, Movement disorders, Xenopus laevis, Epilepsy, 0302 clinical medicine, Genes, X-Linked, Intellectual disability, Missense mutation, Child, Genetics, Genetic Diseases, X-Linked, Syndrome, Middle Aged, White Matter, Pedigree, 3. Good health, Psychiatry and Mental health, Phenotype, Schizophrenia, Child, Preschool, Female, Original Article, medicine.symptom, Function and Dysfunction of the Nervous System, Adult, medicine.medical_specialty, Adolescent, Frameshift mutation, 03 medical and health sciences, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, Chloride Channels, Intellectual Disability, medicine, Animals, Humans, Family, Psychiatry, Molecular Biology, Germ-Line Mutation, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, medicine.disease, 030104 developmental biology, Mood disorders, Cardiovascular and Metabolic Diseases, Mutation, Behavioral medicine, Oocytes, business, Epileptic Syndromes, 030217 neurology & neurosurgery
Abstract

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.Molecular Psychiatry advance online publication, 23 August 2016; doi:10.1038/mp.2016.135. ispartof: Molecular Psychiatry vol:23 issue:2 pages:222-230 ispartof: location:England status: published

Published
2016

36. Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain

Author

Shelagh Joss, Catherine McWilliam, Roman A. Laskowski, Diana Johnson, Miranda Splitt, Janet M. Thornton, Helen V. Firth, Caroline F. Wright, Esther Kinning, and Nidhi Tyagi

Subjects
Male, Models, Molecular, 0301 basic medicine, Developmental Disabilities, Molecular Sequence Data, Protein domain, Population, Mutation, Missense, Gene Expression, Receptors, Cytoplasmic and Nuclear, Population genetics, Sequence alignment, Biology, Protein Structure, Secondary, Genetic Heterogeneity, 03 medical and health sciences, Protein structure, Protein Domains, Genetics, Humans, Missense mutation, Amino Acid Sequence, Child, education, Molecular Biology, Gene, beta Catenin, Genetics (clinical), education.field_of_study, Genetic heterogeneity, Nuclear Proteins, Hydrogen Bonding, Articles, General Medicine, Prognosis, Repressor Proteins, Genetics, Population, 030104 developmental biology, Child, Preschool, Female, Sequence Alignment, Protein Binding
Abstract

We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six new de novo missense diagnoses in TBL1XR1 from the Deciphering Developmental Disorders study, together with population variation data, we show that the β-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely delayed language development, often accompanied by intellectual disability, autism, dysmorphology and gastrointestinal problems. Amino acids affected by likely pathogenic missense mutations are either crucial for the stability of the fold, forming part of a highly conserved symmetrically repeating hydrogen-bonded tetrad, or located at the top face of the β-propeller, where 'hotspot' residues affect the binding of β-catenin to the TBLR1 protein. In contrast, those altered by population variation are significantly less likely to be spatially clustered towards the top face or to be at buried or highly conserved residues. This result is useful not only for interpreting benign and pathogenic missense variants in this gene, but also in other WD40 domains, many of which are associated with disease.

Published
2016

37. Transcriptome: from laboratory to clinic room

Author

Rebecca Amy Dalrymple and Shelagh Joss

Subjects
Messenger RNA, business.industry, Sequence Analysis, RNA, Gene Expression Profiling, Cell, RNA, Computational biology, Transcriptome, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine.anatomical_structure, chemistry, 030225 pediatrics, Pediatrics, Perinatology and Child Health, Gene expression, Medicine, Humans, business, Gene, Function (biology), DNA, Biomarkers
Abstract

‘The “omics” refer to the collective technologies used to characterise and quantify pools of biological molecules and to explore their roles, relationships and actions in the cells of a living creature’.1 Transcriptomics is the study of the abundance of RNA transcripts in a cell or tissue, at a given time. This information adds to our understanding of gene structure, function and biological processes in different tissues and organisms. Other notable ‘omics’: The transcriptome is the total complement of RNA transcripts in a cell.2 RNA is a single-stranded, linear polymer of nucleotides with a ribose group, transcribed (copied) from a DNA template by complementary base pairing. There are many different types of RNA, and the previous concept that ‘DNA makes RNA makes protein’ is now scorned for being too simplistic. Messenger RNA (mRNA) forms the template for protein translation. However, to make fully functioning protein, you also need a range of non-protein coding RNAs. These regulate gene expression depending on the tissue type and a range of external factors. The importance of non-protein coding RNA is recognised increasingly3 (see table 1 for types of RNA and …

Published
2018

38. Corrigendum: Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth

Author

Elise Ruark, Andrea H. Németh, Rob L. M. van Montfort, Jennifer Campbell, Isaac M. Westwood, Anna Elliott, Shelagh Joss, Katrina Tatton-Brown, Chey Loveday, Nazneen Rahman, Anna Zachariou, Emma Ramsay, McKinlay Gardner, Anthony Renwick, and Matthew Clarke

Subjects
Models, Molecular, Genetics, Protein Conformation, business.industry, Protein subunit, Membrane Proteins, General Medicine, Protein phosphatase 2, Articles, Biology, Phenotype, Text mining, Mutation, Humans, Exome, Protein Phosphatase 2, Corrigendum, business, Molecular Biology, Gene, Genetic Association Studies, Growth Disorders, Genetics (clinical)
Abstract

Overgrowth syndromes comprise a group of heterogeneous disorders characterised by excessive growth parameters, often in association with intellectual disability. To identify new causes of human overgrowth, we have been undertaking trio-based exome sequencing studies in overgrowth patients and their unaffected parents. Prioritisation of functionally relevant genes with multiple unique de novo mutations revealed four mutations in protein phosphatase 2A (PP2A) regulatory subunit B family genes protein phosphatase 2, regulatory Subunit B', beta (PPP2R5B); protein phosphatase 2, regulatory Subunit B', gamma (PPP2R5C); and protein phosphatase 2, regulatory Subunit B', delta (PPP2R5D). This observation in 3 related genes in 111 individuals with a similar phenotype is greatly in excess of the expected number, as determined from gene-specific de novo mutation rates (P = 1.43 × 10(-10)). Analysis of exome-sequencing data from a follow-up series of overgrowth probands identified a further pathogenic mutation, bringing the total number of affected individuals to 5. Heterozygotes shared similar phenotypic features including increased height, increased head circumference and intellectual disability. The mutations clustered within a region of nine amino acid residues in the aligned protein sequences (P = 1.6 × 10(-5)). We mapped the mutations onto the crystal structure of the PP2A holoenzyme complex to predict their molecular and functional consequences. These studies suggest that the mutations may affect substrate binding, thus perturbing the ability of PP2A to dephosphorylate particular protein substrates. PP2A is a major negative regulator of v-akt murine thymoma viral oncogene homolog 1 (AKT). Thus, our data further expand the list of genes encoding components of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signalling cascade that are disrupted in human overgrowth conditions.

Published
2018

39. Pathogenicity and selective constraint on variation near splice sites

Author

Sebastian S. Gerety, Frances Flinter, Patrick J. Short, Esther Kinning, Matthew E. Hurles, I. Karen Temple, Diana S. Johnson, Meriel McEntagart, Jeffrey C. Barrett, Bronwyn Kerr, Tabib Dabir, Shelagh Joss, Sofia Douzgou, Giuseppe Gallone, Jill Clayton-Smith, Caroline F. Wright, David R. FitzPatrick, Jeremy F. McRae, Emma McCann, Sally Ann Lynch, Liu He, Wayne Lam, Holly Ironfield, Vivienne McConnell, Virginia Clowes, Elizabeth H. Wynn, Helen V. Firth, and Jenny Lord

Subjects
Proband, Developmental Disabilities, Biology, medicine.disease_cause, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Exome Sequencing, Genetics, medicine, Humans, Exome, splice, Gene, Genetics (clinical), Selection (genetic algorithm), Exome sequencing, 030304 developmental biology, Mutation, 0303 health sciences, Research, RNA splicing, RNA Splice Sites, 030217 neurology & neurosurgery
Abstract

Mutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well as >60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice site, and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking non-canonical positions (27%), and calculated the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at non-canonical positions in splice sites. We estimate 35-40% of pathogenic variants in non-canonical splice site positions are missing from public databases.

Published
2018
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40. 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

41. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Author

Lelliott C, Wendy D Jones, Helen V. Firth, Sebastian S. Gerety, Daniel A. King, Ajith Kumar, Mary O'Regan, Diana Rajan, Nicola Foulds, Judith A. Goodship, Jenny Lord, Angela F. Brady, Dominic J. McMullan, James Whitworth, Cecilia W. Lo, Morad Ansari, Emma Hobson, David R. FitzPatrick, Nadia Akawi, Jeremy F. McRae, Alejandro Sifrim, Peter D. Turnpenny, Shelagh Joss, Deborah Osio, Tomas W Fitzgerald, Caroline F. Wright, Audrey Smith, Richard Francis, Melissa Lees, Elena Prigmore, Charu Deshpande, Jeffrey C. Barrett, Trevor Cole, Stephen Clayton, Meena Balasubramanian, Nikolai Klena, Moira Blyth, George C. Gabriel, Elisabeth Rosser, Ganesh J. Swaminathan, Matthew E. Hurles, and Virginia Piombo

Subjects
Male, Protein-Arginine N-Methyltransferases, Candidate gene, medicine.medical_specialty, Genotype, Ubiquitin-Protein Ligases, Developmental Disabilities, Population, Cell Cycle Proteins, Genes, Recessive, Biology, Compound heterozygosity, Article, symbols.namesake, Genotype-phenotype distinction, Matrix Metalloproteinases, Secreted, Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, education, Genetic Association Studies, Family Health, education.field_of_study, Genetic heterogeneity, Genetic Variation, Sequence Analysis, DNA, United Kingdom, Pedigree, Phenotype, Mendelian inheritance, symbols, Medical genetics, Female, human activities
Abstract

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

Published
2015

42. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

Author

Saskia M. Maas, Frédérique Béna, Koenraad Devriendt, Nathalie Marle, Birgitte Bang, Tjitske Kleefstra, Evan E. Eichler, Andy Willaert, Suzanne Vanhauwaert, Marjolein H. Willemsen, Eva Jacobs, Laurence Faivre, Shelagh Joss, Frank Speleman, Paul Coucke, Ernie M.H.F. Bongers, Abeltje M. Polstra, David A. Koolen, Nina De Rocker, Hilde Peeters, Konstantinos Varvagiannis, Thomy de Ravel, Francesca Novara, Julien Thevenon, Filip Roelens, Nele Bockaert, Sabrina Giglio, Alexander Hoischen, Susan Zeesman, Marjolaine Willems, Zeynep Tümer, Orsetta Zuffardi, Björn Menten, Carla Rosenberg, Sarah Vergult, Małgorzata J.M. Nowaczyk, Teacher Education, Clinical sciences, Medical Genetics, Faculty of Medicine and Pharmacy, Human Genetics, and Paediatric Genetics

Subjects
Adult, Male, Adolescent, Child, preschool, Obesity/genetics, Transcription Factors/genetics, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Gene Expression, Nerve Tissue Proteins, Biology, Bioinformatics, Aquatic organisms, Developmental psychology, Intellectual Disability, Gene Duplication, Intellectual disability, medicine, Animals, Humans, Nerve Tissue Proteins/genetics, Point Mutation, Obesity, Child, Genetic Association Studies, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Chromosome Mapping, Middle Aged, zebrafish, medicine.disease, Intellectual Disability/genetics, facies, Chromosomes, Human, Pair 2, Cohort studies, young adult, Female, Chromosome Deletion, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Transcription Factors
Abstract

Item does not contain fulltext PURPOSE: Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis. METHODS: In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization. RESULTS: Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain. CONCLUSION: Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460-466.

Published
2015

43. A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: A second gene that may contribute to the 1q41-q42 deletion phenotype

Author

Ignazio S. Piras, David Craig, Isabelle Schrauwen, Matt De Both, Chris Balak, Szabolcs Szelinger, Marcus Naymik, Madison LaFleur, Vinodh Narayanan, Ryan Richholt, Koen Devriendt, Tyler Izatt, Matthew J. Huentelman, Shelagh Joss, Sampathkumar Rangasamy, Mary E. Parker, Keri Ramsey, Panieh Terraf, Wayne M. Jepsen, Newell Belnap, Ashley L. Siniard, and Lorida Llaci

Subjects
0301 basic medicine, Proband, Drug Resistant Epilepsy, Developmental Disabilities, Nonsense mutation, Biology, Germline, Frameshift mutation, 03 medical and health sciences, Epilepsy, Intellectual disability, Exome Sequencing, Genetics, medicine, Humans, Exome, Frameshift Mutation, Genetics (clinical), SKP Cullin F-Box Protein Ligases, Microdeletion syndrome, medicine.disease, Body Dysmorphic Disorders, Prognosis, 030104 developmental biology, Phenotype, Chromosomes, Human, Pair 1, Child, Preschool, Mutation (genetic algorithm), Female, Chromosome Deletion
Abstract

Chromosome 1q41-q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41-q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41-q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3-year-old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41-q42 MDS. Through a familial whole-exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41-q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41-q42 gene deletion syndrome.

Published
2017

44. Heterozygous mutations affecting the protein kinase domain of

Author

Mark J, Hamilton, Richard C, Caswell, Natalie, Canham, Trevor, Cole, Helen V, Firth, Nicola, Foulds, Ketil, Heimdal, Emma, Hobson, Gunnar, Houge, Shelagh, Joss, Dhavendra, Kumar, Anne Katrin, Lampe, Isabelle, Maystadt, Victoria, McKay, Kay, Metcalfe, Ruth, Newbury-Ecob, Soo-Mi, Park, Leema, Robert, Cecilie F, Rustad, Emma, Wakeling, Andrew O M, Wilkie, The Deciphering Developmental Disorders, Study, Stephen R F, Twigg, and Mohnish, Suri

Subjects
Male, Models, Molecular, Heterozygote, protein kinases, Adolescent, Developmental Disabilities, Mutation, Missense, Syndrome, congenital heart defects, Protein Domains, cdk13, Intellectual Disability, CDC2 Protein Kinase, Mutation, Humans, Thermodynamics, Female, New Disease Loci, Child, exome sequencing, Conserved Sequence, ohdo syndrome
Abstract

Introduction Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations. Methods Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause. Results Our cohort comprised 16 individuals aged 4–16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898–1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain. Conclusions These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

Published
2017

45. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Margaret F. Lippincott, Diane Lucente, Catarina M. Seabra, Shelagh Joss, Hemant Bengani, Angela Lek, Klaus W. Ruprecht, Jenny Jing, Nicholas Katsanis, Joe Rainger, Tammy Kammin, Cynthia C. Morton, Ravikumar Balasubramanian, Chie Hee Cho, Peter L. Jones, Alexandra Silva, Ianina Scheer, Jennifer R. Law, Nobuhiko Okamoto, Stephanie B. Seminara, William F. Crowley, Joseph A. Marsh, Jeanie B. Tryggestad, Markus Zweier, Benjamin Currall, Veronica van Heyningen, Serkan Erdin, Natalie D. Shaw, Michael E. Talkowski, John Graham, Daniel G. MacArthur, Kathleen A. Williamson, Morad Ansari, Angela M. Kaindl, Nirav J. Patel, Jacqueline K. Rainger, Zachary A. Kupchinsky, Koh-ichiro Yoshiura, Kaitlin E. Samocha, Angela E. Lin, Daisuke Sato, Bart Loeys, Malik Nassan, Sylvia S. Singh, Takako I. Jones, Eric C. Liao, Donncha S. Dunican, Claudia Cesaretti, Lisa A. Schimmenti, Janet E. Hall, Christina Jacobsen, Ryan L. Collins, Jill Clayton Smith, Alexei Stortchevoi, Erica E. Davis, Tatiana Pineda Buitrago, Shahrin Pereira, Masato Shino, Steven A. Moore, Wolfgang Mühlbauer, Anita Rauch, James F. Gusella, Colby Chiang, Nalton F. Ferraro, José Elías García-Ortiz, David R. FitzPatrick, Alain Verloes, Katharina Steindl, Jodi D. Hoffman, Yu An, Lacey Plummer, Benjamin Brasseur, Monkol Lek, Richard R. Meehan, Orlando Perez Silva, Harrison Brand, Steven D. Chernausek, and Jason R. Willer

Subjects
Male, 0301 basic medicine, Proband, Adolescent, Chromosomal Proteins, Non-Histone, Nose, medicine.disease_cause, Choanal Atresia, Muscular Dystrophies, Article, 03 medical and health sciences, 0302 clinical medicine, Journal Article, Genetics, medicine, Humans, Microphthalmos, Facioscapulohumeral muscular dystrophy, Missense mutation, Genetic Predisposition to Disease, Muscular dystrophy, Craniofacial, Child, Zebrafish, Mutation, biology, Infant, medicine.disease, biology.organism_classification, Phenotype, 030104 developmental biology, Child, Preschool, Female, Human medicine, 030217 neurology & neurosurgery, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Published
2017

46. Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1

Author

Tabib Dabir, Roman A. Laskowski, Shelagh Joss, Jenny Morton, Janet M. Thornton, Caroline F. Wright, Jochem M. G. Evers, Jill Clayton-Smith, Miranda Splitt, Meriel McEntagart, Dragana Josifova, Bronwyn Kerr, Alison Kraus, Audrey Smith, Mohnish Suri, Kate Baker, Sinéad O’Brien, Baker, Kate [0000-0003-2986-0584], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, syntaxin‐binding protein 1, syntaxin-binding protein 1, Protein domain, Population, Biology, Munc18, 03 medical and health sciences, 0302 clinical medicine, Exome Aggregation Consortium, genomics, Genetics, STXBP1, Missense mutation, Genetics(clinical), protein structure, education, Exome, Gene, Molecular Biology, Genetics (clinical), Loss function, education.field_of_study, Epilepsy, Original Articles, 3. Good health, 030104 developmental biology, epilepsy, Original Article, Haploinsufficiency, 030217 neurology & neurosurgery
Abstract

Background Syntaxin-binding protein 1, encoded by STXBP1, is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss-of-function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype–phenotype correlations. Methods We report 11 patients with pathogenic de novo mutations in STXBP1 identified in the first 4293 trios of the Deciphering Developmental Disorder (DDD) study, including six missense variants. We analyzed the structural locations of the pathogenic missense variants from this study and the literature, as well as population missense variants extracted from Exome Aggregation Consortium (ExAC). Results Pathogenic variants are significantly more likely to occur at highly conserved locations than population variants, and be buried inside the protein domain. Pathogenic mutations are also more likely to destabilize the domain structure compared with population variants, increasing the proportion of (partially) unfolded domains that are prone to aggregation or degradation. We were unable to detect any genotype–phenotype correlation, but unlike previously reported cases, most of the DDD patients with STXBP1 pathogenic variants did not present with very early-onset or severe epilepsy and encephalopathy, though all have developmental delay with intellectual disability and most display behavioral problems and suffered seizures in later childhood. Conclusion Variants across STXBP1 that cause loss of function can result in severe intellectual disability with or without seizures, consistent with a haploinsufficiency mechanism. Pathogenic missense mutations act through destabilization of the protein domain, making it prone to aggregation or degradation. The presence or absence of early seizures may reflect ascertainment bias in the literature as well as the broad recruitment strategy of the DDD study.

Published
2017

47. How to use… microarray comparative genomic hybridisation to investigate developmental disorders

Author

Shelagh Joss, John Tolmie, and Mira Kharbanda

Subjects
Comparative Genomic Hybridization, medicine.medical_specialty, Microarray, business.industry, Developmental Disabilities, Computational biology, medicine.disease, Clinical Practice, Pediatrics, Perinatology and Child Health, Chromosomal Structure, Humans, Medicine, Medical genetics, Autism, Clinical significance, Child, business, Psychiatry, Oligonucleotide Array Sequence Analysis
Abstract

Array-comparative genomic hybridisation (array-CGH) is a relatively new test that permits close scrutiny of chromosomal structure to detect genomic microdeletions and microduplications that are invisible in a conventional karyotype. Array-CGH is now the 'first-line' genetic test in the investigation of early developmental impairments and learning difficulties, especially if the clinical picture includes dysmorphism, abnormal growth, congenital anomalies, epilepsy and autism, alone or in combination. However, due to the array-CGH report's technical content and the uncertain clinical significance of many genomic findings, the results of array-CGH studies need careful interpretation. Array-CGH trebles the frequency of diagnosis compared with conventional karyotyping, but collaborative working, involving paediatricians, clinical geneticists and clinical scientists, is most important for interpretation of the results of new genomic investigations in everyday clinical practice.

Published
2014

48. An emerging phenotype of Xq22 microdeletions in females with severe intellectual disability, hypotonia and behavioral abnormalities

Author

Bertrand Isidor, Anna Erlandsson, Lena Samuelsson, Shelagh Joss, Shino Shimada, Cédric Le Caignec, Mohnish Suri, Margarita Stefanova, Noriko Sangu, Anna Wilsdon, Keiko Shimojima, and Toshiyuki Yamamoto

Subjects
medicine.medical_specialty, Muscle Hypotonia, Adolescent, Genotype, Chromosomes, Human, Pair 22, Behavioral Symptoms, Biology, Genotype-phenotype distinction, X Chromosome Inactivation, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Child, Myelin Proteolipid Protein, Sex Chromosome Aberrations, Genetics (clinical), Sequence Deletion, Base Sequence, Infant, Microdeletion syndrome, medicine.disease, Phenotype, Hypotonia, Child, Preschool, Medical genetics, Female, medicine.symptom
Abstract

The majority of Xq22 duplications seen in patients with Pelizaeus-Merzbacher disease (PMD) include proteolipid protein 1 (PLP1), the gene responsible for PMD, and neighboring genes. Some cases result from larger duplications up to 7 Mb in size. In comparison, the deletions including PLP1 seen in PMD patients are small. In this study, we present the genetic and clinical information for five female patients with deletions involving the Xq22 region, and review the correlation between the genotype and phenotype. Three of the five patients show similar large deletions (>3 Mb) ranging from Xq22.1 to Xq22.3 and all manifest severe intellectual disability, hypotonia and behavioral abnormalities. The most striking similarity among them are the behavioral problems, including poor eye contact and sleep disturbance. We propose that this represents an emerging distinctive microdeletion syndrome encompassing PLP1 in female patients. The possible candidate region responsible for such distinctive features has been narrowed down to the neighboring region for PLP1, including the interleukin 1 receptor accessory protein-like 2 (IL1RAPL2) gene and the clustered brain expressed X-linked (BEX) genes. The gene(s) responsible for severe neurological features in the patients in this study would be located in the regions proximate to PLP1; thus, males with the deletions involving the gene(s) would be lethal, and finally, the sizes of the deletions in PMD patients would be smaller than those of the duplications.

Published
2014

49. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Author

Hamdan, Fadi F., primary, Myers, Candace T., additional, Cossette, Patrick, additional, Lemay, Philippe, additional, Spiegelman, Dan, additional, Laporte, Alexandre Dionne, additional, Nassif, Christina, additional, Diallo, Ousmane, additional, Monlong, Jean, additional, Cadieux-Dion, Maxime, additional, Dobrzeniecka, Sylvia, additional, Meloche, Caroline, additional, Retterer, Kyle, additional, Cho, Megan T., additional, Rosenfeld, Jill A., additional, Bi, Weimin, additional, Massicotte, Christine, additional, Miguet, Marguerite, additional, Brunga, Ledia, additional, Regan, Brigid M., additional, Mo, Kelly, additional, Tam, Cory, additional, Schneider, Amy, additional, Hollingsworth, Georgie, additional, FitzPatrick, David R., additional, Donaldson, Alan, additional, Canham, Natalie, additional, Blair, Edward, additional, Kerr, Bronwyn, additional, Fry, Andrew E., additional, Thomas, Rhys H., additional, Shelagh, Joss, additional, Hurst, Jane A., additional, Brittain, Helen, additional, Blyth, Moira, additional, Lebel, Robert Roger, additional, Gerkes, Erica H., additional, Davis-Keppen, Laura, additional, Stein, Quinn, additional, Chung, Wendy K., additional, Dorison, Sara J., additional, Benke, Paul J., additional, Fassi, Emily, additional, Corsten-Janssen, Nicole, additional, Kamsteeg, Erik-Jan, additional, Mau-Them, Frederic T., additional, Bruel, Ange-Line, additional, Verloes, Alain, additional, Õunap, Katrin, additional, Wojcik, Monica H., additional, Albert, Dara V.F., additional, Venkateswaran, Sunita, additional, Ware, Tyson, additional, Jones, Dean, additional, Liu, Yu-Chi, additional, Mohammad, Shekeeb S., additional, Bizargity, Peyman, additional, Bacino, Carlos A., additional, Leuzzi, Vincenzo, additional, Martinelli, Simone, additional, Dallapiccola, Bruno, additional, Tartaglia, Marco, additional, Blumkin, Lubov, additional, Wierenga, Klaas J., additional, Purcarin, Gabriela, additional, O’Byrne, James J., additional, Stockler, Sylvia, additional, Lehman, Anna, additional, Keren, Boris, additional, Nougues, Marie-Christine, additional, Mignot, Cyril, additional, Auvin, Stéphane, additional, Nava, Caroline, additional, Hiatt, Susan M., additional, Bebin, Martina, additional, Shao, Yunru, additional, Scaglia, Fernando, additional, Lalani, Seema R., additional, Frye, Richard E., additional, Jarjour, Imad T., additional, Jacques, Stéphanie, additional, Boucher, Renee-Myriam, additional, Riou, Emilie, additional, Srour, Myriam, additional, Carmant, Lionel, additional, Lortie, Anne, additional, Major, Philippe, additional, Diadori, Paola, additional, Dubeau, François, additional, D’Anjou, Guy, additional, Bourque, Guillaume, additional, Berkovic, Samuel F., additional, Sadleir, Lynette G., additional, Campeau, Philippe M., additional, Kibar, Zoha, additional, Lafrenière, Ronald G., additional, Girard, Simon L., additional, Mercimek-Mahmutoglu, Saadet, additional, Boelman, Cyrus, additional, Rouleau, Guy A., additional, Scheffer, Ingrid E., additional, Mefford, Heather C., additional, Andrade, Danielle M., additional, Rossignol, Elsa, additional, Minassian, Berge A., additional, and Michaud, Jacques L., additional

Published
2017
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50. RASA1Mutations and Associated Phenotypes in 68 Families with Capillary Malformation-Arteriovenous Malformation

Author

Marc Abramowicz, Felicity Collins, Philippe Clapuyt, Christine Léauté-Labrèze, Brid O'Donnell, Julie Désir, Eulalia Baselga, María Antonia González-Enseñat, Antonella Mendola, Nicola Brunetti-Pierri, Yim Dwight, Nicole Revencu, Victoria R. Barrio, David J.E. Lord, Lesley C. Adès, David J. Amor, Mariarosaria Cozzolino, Orli Wargon, Shelagh Joss, Frank Hammer, Susan J. Bayliss, Josée Dubois, Didier Bessis, María del Carmen Boente, Leona Fishman, Wendy K. Chung, Miikka Vikkula, Oon T. Tan, Yolanda Gilaberte, Laurence M. Boon, Cheryl Cytrynbaum, Juliette Mazereeuw-Hautier, Carol A. Gardiner, Patricia E. Burrows, Sarah A. Sandaradura, Fred Ghali, Maria R. Cordisco, Alan D. Irvine, Asunción Vicente, Catheline Vilain, John B. Mulliken, Aicha Salhi, Francine Blei, Loreto Martorell, Anne Dompmartin, Janine Smith, Ashley Wilson, S. Syed, Sarah L. Chamlin, Ana Martín-Santiago, Marie Ange Delrue, Reed E. Pyeritz, Revencu, N, Boon, Lm, Mendola, A, Cordisco, Mr, Dubois, J, Clapuyt, P, Hammer, F, Amor, Dj, Irvine, Ad, Baselga, E, Dompmartin, A, Syed, S, Martin Santiago, A, Ades, L, Collins, F, Smith, J, Sandaradura, S, Barrio, Vr, Burrows, Pe, Blei, F, Cozzolino, M, BRUNETTI PIERRI, Nicola, Vicente, A, Abramowicz, M, D?sir, J, Vilain, C, Chung, Wk, Wilson, A, Gardiner, Ca, Dwight, Y, Lord, Dj, Fishman, L, Cytrynbaum, C, Chamlin, S, Ghali, F, Gilaberte, Y, Joss, S, Boente Mdel, C, L?aut? Labr?ze, C, Delrue, Ma, Bayliss, S, Martorell, L, Gonz?lez Ense?at, Ma, Mazereeuw Hautier, J, O'Donnell, B, Bessis, D, Pyeritz, Re, Salhi, A, Tan, Ot, Wargon, O, Mulliken, Jb, and Vikkula, M.

Subjects
Male, Pathology, medicine.medical_specialty, Capillary malformation, DNA Mutational Analysis, Port-Wine Stain, Sturge–Weber syndrome, arteriovenous malformation, P120 GTPase Activating Protein, Sturge-Weber syndrome, Biology, medicine.disease_cause, Arteriovenous Malformations, Gene Order, Genetics, medicine, Humans, Prospective Studies, Allele, Genetic Association Studies, Genetics (clinical), Retrospective Studies, Mutation, capillary malformation, p120 GTPase Activating Protein, Arteriovenous malformation, medicine.disease, Parkes Weber syndrome, Capillaries, Glomuvenous malformation, Phenotype, Amino Acid Substitution, Female, RASA1
Abstract

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n=100), common CM(s) (port-wine stain; n=100), Sturge-Weber syndrome (n=37), or isolated AVM(s) (n=24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the second-hit hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up. (C) 2013 Wiley Periodicals, Inc.

Published
2013

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