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1. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology

Author: Andrew K. Sobering, Laura M. Bryant, Dong Li, Julie McGaughran, Isabelle Maystadt, Stephanie Moortgat, John M. Graham, Jr., Arie van Haeringen, Claudia Ruivenkamp, Roos Cuperus, Julie Vogt, Jenny Morton, Charlotte Brasch-Andersen, Maria Steenhof, Lars Kjærsgaard Hansen, Élodie Adler, Stanislas Lyonnet, Veronique Pingault, Marlin Sandrine, Alban Ziegler, Tyhiesia Donald, Beverly Nelson, Brandon Holt, Oleksandra Petryna, Helen Firth, Kirsty McWalter, Jacob Zyskind, Aida Telegrafi, Jane Juusola, Richard Person, Michael J. Bamshad, Dawn Earl, Anne Chun-Hui Tsai, Katherine R. Yearwood, Elysa Marco, Catherine Nowak, Jessica Douglas, Hakon Hakonarson, and Elizabeth J. Bhoj
Subjects: Genetics, QH426-470
Published: 2023
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2. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology

Author: Andrew K. Sobering, Laura M. Bryant, Dong Li, Julie McGaughran, Isabelle Maystadt, Stephanie Moortgat, John M. Graham, Jr., Arie van Haeringen, Claudia Ruivenkamp, Roos Cuperus, Julie Vogt, Jenny Morton, Charlotte Brasch-Andersen, Maria Steenhof, Lars Kjærsgaard Hansen, Élodie Adler, Stanislas Lyonnet, Veronique Pingault, Marlin Sandrine, Alban Ziegler, Tyhiesia Donald, Beverly Nelson, Brandon Holt, Oleksandra Petryna, Helen Firth, Kirsty McWalter, Jacob Zyskind, Aida Telegrafi, Jane Juusola, Richard Person, Michael J. Bamshad, Dawn Earl, Anne Chun-Hui Tsai, Katherine R. Yearwood, Elysa Marco, Catherine Nowak, Jessica Douglas, Hakon Hakonarson, and Elizabeth J. Bhoj
Subjects: PHF8, X-linked intellectual disability, orofacial clefting, epigenetic gene regulation, histone demethylation, Genetics, QH426-470
Abstract: Summary: Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function.
Published: 2022
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3. COLEC10 is mutated in 3MC patients and regulates early craniofacial development.

Author: Mustafa M Munye, Anna Diaz-Font, Louise Ocaka, Maiken L Henriksen, Melissa Lees, Angela Brady, Dagan Jenkins, Jenny Morton, Soren W Hansen, Chiara Bacchelli, Philip L Beales, and Victor Hernandez-Hernandez
Subjects: Genetics, QH426-470
Abstract: 3MC syndrome is an autosomal recessive heterogeneous disorder with features linked to developmental abnormalities. The main features include facial dysmorphism, craniosynostosis and cleft lip/palate; skeletal structures derived from cranial neural crest cells (cNCC). We previously reported that lectin complement pathway genes COLEC11 and MASP1/3 are mutated in 3MC syndrome patients. Here we define a new gene, COLEC10, also mutated in 3MC families and present novel mutations in COLEC11 and MASP1/3 genes in a further five families. The protein products of COLEC11 and COLEC10, CL-K1 and CL-L1 respectively, form heteromeric complexes. We show COLEC10 is expressed in the base membrane of the palate during murine embryo development. We demonstrate how mutations in COLEC10 (c.25C>T; p.Arg9Ter, c.226delA; p.Gly77Glufs*66 and c.528C>G p.Cys176Trp) impair the expression and/or secretion of CL-L1 highlighting their pathogenicity. Together, these findings provide further evidence linking the lectin complement pathway and complement factors COLEC11 and COLEC10 to morphogenesis of craniofacial structures and 3MC etiology.
Published: 2017
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4. Identifying phenotypic expansions for congenital diaphragmatic hernia plus ( <scp>CDH</scp> +) using <scp>DECIPHER</scp> data

Author: Amy Hardcastle, Aliska M. Berry, Ian M. Campbell, Xiaonan Zhao, Pengfei Liu, Amanda E. Gerard, Jill A. Rosenfeld, Saumya D. Sisoudiya, Andres Hernandez‐Garcia, Sara Loddo, Silvia Di Tommaso, Antonio Novelli, Maria L. Dentici, Rossella Capolino, Maria C. Digilio, Ludovico Graziani, Cecilie F. Rustad, Katherine Neas, Giovanni B. Ferrero, Alfredo Brusco, Eleonora Di Gregorio, Diana Wellesley, Claire Beneteau, Madeleine Joubert, Kris Van Den Bogaert, Anneleen Boogaerts, Dominic J. McMullan, John Dean, Maria G. Giuffrida, Laura Bernardini, Vinod Varghese, Nora L. Shannon, Rachel E. Harrison, Wayne W. K. Lam, Shane McKee, Peter D. Turnpenny, Trevor Cole, Jenny Morton, Jacqueline Eason, Marilyn C. Jones, Rebecca Hall, Michael Wright, Karen Horridge, Chad A. Shaw, Wendy K. Chung, and Daryl A. Scott
Subjects: DNA Copy Number Variations, Diaphragm, USP9X, CREBBP, DECIPHER database, SMARCA4, UBA2, congenital diaphragmatic hernia, Mice, Genetics, Animals, Hernias, Diaphragmatic, Congenital, Genetics (clinical)
Abstract: Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.
Published: 2022
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5. Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

Author: Meena Balasubramanian, Sunwoo Lee, Eguzkine Ochoa, Magdalena Badura-Stronka, Deirdre Donnelly, Damien Lederer, Sally Lynch, Alice Gardham, Jenny Morton, Helen Stewart, France Docquier, Fay Rodger, Jose Martin, Ana Toribio, and Eamonn Maher
Abstract: HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for > 2M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.
Published: 2023
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6. Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants

Author: Glen D. Thomson, Olga Calabrese, Hong Cui, Sandra Chantot Bastaraud, Frances Elmslie, Renee Carroll, Agnès Guët, Sandra Whalen, Anne Slavotinek, Thierry Billette de Villemeur, Vishal Kumar, Brian Kirmse, Patrick Yap, Elise Brischoux-Boucher, Florence Riccardi, Jenny Morton, Carroll Jennifer, Jonathan Levy, Manoelle Kossorotoff, Alessandro Mauro Spinelli, Elisabeth Forsythe, Annelies Dheedene, Anne McCabe, Cecile Cieuta Walti, Jozef Gecz, Anne Claude Tabet, Laurent Villard, Cyril Mignot, Kristen V. Truxal, Jessica N. Hartley, Annick Raas-Rothschild, Jillian R Ozmore, Marie Shaw, Jan Liebelt, Delphine Héron, Patrick Frosk, Benjamin Kamien, Jane A. Hurst, Antonella Pini, UF de Génétique Clinique et Centre de Reference Anomalies du Développement et Syndromes Malformatifs, Sorbonne Université (SU), University of Adelaide, Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Sherbrooke (UdeS), Women’s and Children’s Hospital [Adelaide], St George’s University Hospitals, Genetic Health Service New Zealand, Great Ormond Street Hospital for Children NHS Foundation Trust, Partenaires INRAE, University of Mississippi Medical Center (UMMC), Dartmouth Hitchcock Medical Center, University of Modena and Reggio Emilia, Hôpital Robert Debré, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Necker, King-Edward Memorial Hospital, Perth, Australia., Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Chaim Sheba Medical Center, IRCCS Istituto delle Scienze Neurologiche di Bologna [Bologna, Italy], Ospedale Bellaria [Bologna, Italy], University of Manitoba [Winnipeg], University of California, Ohio State University [Columbus] (OSU), Ghent University Hospital, GeneDx [Gaithersburg, MD, USA], Starship Children's Hospital, University of Auckland [Auckland], 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), NHMRC grants APP1155224 and APP1091593 and Channel 7 Children’s Research Foundation, National Human Genome Research Institute of the National Institutes of Health under Award Number U01HG009599, Gall, Valérie, University of California (UC), ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)
Subjects: Male, Care4Rare Canada Consortium, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Deafness, Loss of Function Mutation, Intellectual disability, Genetics research, 2.1 Biological and endogenous factors, Medicine, Missense mutation, Aetiology, Child, Genetics (clinical), Genetics & Heredity, Dystonia, Genetics, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Liver Disease, 030305 genetics & heredity, Neurodevelopmental disorders, Syndrome, Phenotype, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], Child, Preschool, Medical genetics, Female, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Clinical Sciences, Mutation, Missense, Asymptomatic, Article, 03 medical and health sciences, Rare Diseases, Clinical Research, Intellectual Disability, Humans, Preschool, Loss function, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Neurosciences, Membrane Proteins, medicine.disease, Brain Disorders, Xq28, Hereditary Central Nervous System Demyelinating Diseases, Mutation, Missense, Digestive Diseases, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.
Published: 2021
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7. Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders

Author: Simon J. McGowan, Jenny Morton, Eduardo Calpena, David W. Johnson, Richard P. Lifton, Pascal Maire, Andrew O.M. Wilkie, Stephen R.F. Twigg, Michael L. Cunningham, Rodrigo Atique, Andrew T. Timberlake, Jonas A Gustafson, Steven A. Wall, Maud Wurmser, Débora Romeo Bertola, and Maria Rita Passos-Bueno
Subjects: 0301 basic medicine, Proband, DNA Mutational Analysis, Calvaria, Biology, Bilambdoid synostosis, Craniosynostosis, Cohort Studies, Craniosynostoses, Mice, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Animals, Humans, Missense mutation, RNA-Seq, Exome, Genetic Association Studies, Genetics (clinical), Homeodomain Proteins, Whole Genome Sequencing, Genotype-Phenotype Correlations, MUTAÇÃO GENÉTICA, Infant, Cranial Sutures, Synostosis, medicine.disease, Phenotype, Pedigree, 030104 developmental biology, medicine.anatomical_structure, musculoskeletal diseases, Child, Preschool, 030217 neurology & neurosurgery
Abstract: BackgroundPathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported.MethodsWe investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1nLacZ/+ reporter mouse.ResultsFrom 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme.ConclusionCraniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal±lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis.
Published: 2021
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8. Expanding the phenotype of biallelic loss‐of‐function variants in the <scp> NSUN2 </scp> gene: Description of four individuals with juvenile cataract, chronic nephritis, or brain anomaly as novel complications

Author: Alan R. Lehmann, Jenny Morton, Yuichiro Hara, Tomoo Ogi, Seiji Mizuno, Kohji Kato, Miho Toyama, and Evangeline Wasmer
Subjects: Delayed puberty, Genetics, Microcephaly, Juvenile cataract, business.industry, Genetic disorder, medicine.disease, Compound heterozygosity, Frameshift mutation, Intellectual disability, medicine, medicine.symptom, business, Genetics (clinical), Loss function
Abstract: The NSUN2 gene encodes a tRNA cytosine methyltransferase that functions in the maturation of leucyl tRNA (Leu) (CAA) precursors, which is crucial for the anticodon-codon pairing and correct translation of mRNA. Biallelic loss of function variants in NSUN2 are known to cause moderate to severe intellectual disability. Microcephaly, postnatal growth retardation, and dysmorphic facial features are common complications in this genetic disorder, and delayed puberty is occasionally observed. Here, we report four individuals, two sets of siblings, with biallelic loss-of-function variants in the NSUN2 gene. The first set of siblings have compound heterozygous frameshift variants: c.546_547insCT, p.Met183Leufs*13; c.1583del, p.Pro528Hisfs*19, and the other siblings carry a homozygous frameshift variant: c.1269dup, p.Val424Cysfs*14. In addition to previously reported clinical features, the first set of siblings showed novel complications of juvenile cataract and chronic nephritis. The other siblings showed hypomyelination and simplified gyral pattern in neuroimaging. NSUN2-related intellectual disability is a very rare condition, and less than 20 cases have been reported previously. Juvenile cataract, chronic nephritis, and brain anomaly shown in the present patients have not been previously described. Our report suggests clinical diversity of NSUN2-related intellectual disability.
Published: 2020
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9. SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Author: Irene M.J. Mathijssen, Helen Lord, Wanda Lattanzi, Stephen R.F. Twigg, Andrew O.M. Wilkie, Nils Koelling, David W. Johnson, Eduardo Calpena, Astrid Weber, Araceli Cuellar, Sigrid M. A. Swagemakers, Jenny Morton, Deborah J. Shears, Julie M. Phipps, Tracy Lester, Simeon A. Boyadjiev, Simon J. McGowan, Sofia Douzgou, Louise C. Wilson, Michael L. Cunningham, Steven A. Wall, Meena Balasubramanian, Krithi Bala, Pathology, and Plastic and Reconstructive Surgery and Hand Surgery
Subjects: Genotype, Smad6 Protein, Mutation, Missense, SMAD6, BMP2, metopic synostosis, digenic inheritance, two-locus, protein instability, Penetrance, Biology, Article, Craniosynostosis, 03 medical and health sciences, Craniosynostoses, 0302 clinical medicine, Genotype-phenotype distinction, medicine, Missense mutation, Metopic synostosis, Humans, Settore BIO/13 - BIOLOGIA APPLICATA, Genotyping, Genetics (clinical), 030304 developmental biology, Genetics, 0303 health sciences, Correction, medicine.disease, Phenotype, 030217 neurology & neurosurgery
Abstract: Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism near BMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P
Published: 2020

10. Variants in

Author: Andrew K, Sobering, Laura M, Bryant, Dong, Li, Julie, McGaughran, Isabelle, Maystadt, Stephanie, Moortgat, John M, Graham, Arie, van Haeringen, Claudia, Ruivenkamp, Roos, Cuperus, Julie, Vogt, Jenny, Morton, Charlotte, Brasch-Andersen, Maria, Steenhof, Lars Kjærsgaard, Hansen, Élodie, Adler, Stanislas, Lyonnet, Veronique, Pingault, Marlin, Sandrine, Alban, Ziegler, Tyhiesia, Donald, Beverly, Nelson, Brandon, Holt, Oleksandra, Petryna, Helen, Firth, Kirsty, McWalter, Jacob, Zyskind, Aida, Telegrafi, Jane, Juusola, Richard, Person, Michael J, Bamshad, Dawn, Earl, Anne Chun-Hui, Tsai, Katherine R, Yearwood, Elysa, Marco, Catherine, Nowak, Jessica, Douglas, Hakon, Hakonarson, and Elizabeth J, Bhoj
Abstract: Loss-of-function variants in
Published: 2021

11. Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment

Author: Sangmoon Lee, Ryojun Takeda, Nataliya Di Donato, Masashige Bando, Darina Prchalova, Mathieu Quesnel-Vallières, Seiji Mizuno, Naomichi Matsumoto, Koji Masuda, Miroslava Hancarova, Margaret Harr, Karl Hackmann, Zdenek Sedlacek, Alica Valachova, Alyssa Ritter, Eriko Nishi, Tommaso Pippucci, Michiko Arakawa, Katsuhiko Shirahige, Katsunori Fujiki, Elaine H. Zackai, Noriko Miyake, Marketa Vlckova, Ryuichiro Nakato, Aiko Iwata-Otsubo, Yoseph Barash, Christoph Seiler, Dong Li, Beth Keena, Nobuhiko Okamoto, Kosuke Izumi, Jung Min Ko, Sarah K. Fiordaliso, Elizabeth J. Bhoj, Hakon Hakonarson, Murim Choi, and Jenny Morton
Subjects: 0301 basic medicine, Transcription, Genetic, Mutation, Missense, Down-Regulation, Biology, Histone Deacetylases, Transcriptome, 03 medical and health sciences, Exon, 0302 clinical medicine, Genes, X-Linked, Report, Genetics, Transcriptional regulation, Animals, Humans, Missense mutation, Cognitive Dysfunction, Amino Acid Sequence, Gene, Zebrafish, Genetics (clinical), X chromosome, Spliceosomal complex, Exons, biology.organism_classification, Repressor Proteins, 030104 developmental biology, Gene Expression Regulation, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.
Published: 2019
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12. 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
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13. Dissection of contiguous gene effects for deletions around ERF on chromosome 19

Author: Diana Johnson, Eduardo Calpena, Fiona Blanco Kelly, Elise Boudry-Labis, Anne Dieux-Coeslier, Rachel Harrison, Jenny Morton, Simon J. McGowan, Helen Stewart, Stephen R.F. Twigg, Pradeep C. Vasudevan, Andrew O.M. Wilkie, and Katherine Lachlan
Subjects: Heterozygote, Microarray, Haploinsufficiency, Biology, Craniosynostosis, 03 medical and health sciences, Chromosome 19, Intellectual Disability, Genetics, medicine, Humans, Craniofacial, Child, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, ETS transcription factor family, 030305 genetics & heredity, medicine.disease, Repressor Proteins, Dissection, Mutation, Chromosome Deletion, Chromosomes, Human, Pair 19
Abstract: Heterozygous intragenic loss-of-function mutations of ERF, encoding an ETS transcription factor, were previously reported to cause a novel craniosynostosis syndrome, suggesting that ERF is haploinsufficient. We describe six families harboring heterozygous deletions including, or near to, ERF, of which four were characterized by whole-genome sequencing and two by chromosomal microarray. Based on the severity of associated intellectual disability (ID), we identify three categories of ERF-associated deletions. The smallest (32 kb) and only inherited deletion included two additional centromeric genes and was not associated with ID. Three larger deletions (264–314 kb) that included at least five further centromeric genes were associated with moderate ID, suggesting that deletion of one or more of these five genes causes ID. The individual with the most severe ID had a more telomerically extending deletion, including CIC, a known ID gene. Children found to harbor ERF deletions should be referred for craniofacial assessment, to exclude occult raised intracranial pressure.
Published: 2021

14. DLG4-related synaptopathy: a new rare brain disorder

Author: Edgard Verdura, Alex MacKenzie, Rolph Pfundt, Tobias B. Haack, Ange Line Bruel, Paulino Gómez-Puertas, Anna C.E. Hurst, Bert B.A. de Vries, Stella A. de Man, Maria Johansson Soller, Bregje W.M. van Bon, Elisabeth Sarrazin, Agustí Rodríguez-Palmero, Stephan Waldmüller, Melanie O’Leary, Anne Sophie Denommé-Pichon, Bitten Schönewolf-Greulich, Joseph T. Shieh, V. A. Bjerregaard, Vahid Bahrambeigi, Malin Kvarnung, Agatha Schlüter, Anne Marie Bisgaard, Ingrid M.B.H. van de Laar, Elisa Giorgio, Lars Feuk, Mieke M. van Haelst, Thomas D. Challman, Ineke van de Burgt, Sulagna Kushary, Simone F. Reiter, David B. Everman, Zeynep Tümer, Giorgia Mandrile, Conny M. A. van Ravenswaaij-Arts, Charles Shaw-Smith, Juliane Hoyer, Chad R. Haldeman-Englert, Lotte Kleinendorst, Bryce A. Mendelsohn, Anna Lindstrand, Christine Coubes, Gea Beunders, Sixto García-Miñaur, Antonio Vitobello, Melissa Maria Boerrigter, Alysia Kern Lovgren, Anya Revah-Politi, Carlos E. Prada, Bertrand Isidor, Elena Repnikova, Stephanie Spranger, Esmée van Drie, Frédéric Tran Mau-Them, Zohra Shad, Ben Pode-Shakked, Aurora Pujol, Christiane Zweier, Bjørn Ivar Haukanes, David Gómez-Andrés, Kathleen A. Leppig, Marta Pacio-Míguez, Motti Shohat, Yuval Landau, Benjamin Cogné, Frances Elmslie, Kimberly A. Aldinger, Anita Rauch, Juliann M. Savatt, Nicolas Gruchy, Sharon Whiting, William B. Dobyns, Thomas J. Dye, Sebastien Moutton, Heidi Thiese, Setareh Moghadasi, Iñigo Marcos-Alcalde, Jenny Morton, Sumit Parikh, María Palomares-Bralo, Stéphanie Arpin, Tracy S. Gertler, Meredith J. Ross, Bernt Popp, Amelie J. Müller, Claudia A. L. Ruivenkamp, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Hospital Universitario Germans Trias I Pujol, Vall d'Hebron University Hospital [Barcelona], Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Department of Molecular and Human Genetics (Baylor College of Medicine), Baylor College of Medecine, Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical Genetics, Human Genetics, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], 030105 genetics & heredity, Biology, 03 medical and health sciences, Intellectual Disability, Intellectual disability, medicine, Missense mutation, Humans, Global developmental delay, Exome, Genetics (clinical), Genetics, Brain Diseases, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Brain, medicine.disease, 030104 developmental biology, Phenotype, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Autism spectrum disorder, Neurodevelopmental Disorders, Synaptopathy, DLG4, Postsynaptic density, Disks Large Homolog 4 Protein
Abstract: Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access) PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
Published: 2021
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15. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay

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

16. A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis

Author: Julie M. Phipps, Jenny Morton, Elizabeth Sweeney, Araceli Cuellar, Jeremy A. Sabourin, Assen Bussarsky, Val C. Sheffield, James L. Mills, Michael L. Cunningham, David W. Johnson, Karen Crawford, Krithi Bala, Mary M. Jenkins, Marta Barba, Louise C. Wilson, Cristina M. Justice, Nadezhda Yaneva, Lawrence C. Brody, Simeon A. Boyadjiev, Paul A. Romitti, Katie E. M. Rees, Andrew O.M. Wilkie, Wanda Lattanzi, Peter H. Langlois, Peter Noons, Yan Zhou, Rachel K. Tittle, Steven A. Wall, Tony Roscioli, Marike Zwienenberg, Denise M. Kay, Deirdre Cilliers, Kiril Georgiev, Jo C. Byren, Robert J. Sicko, Craig W. Senders, Lorenzo D. Botto, Alexander F. Wilson, Radka Kaneva, E Simeonov, Astrid Weber, Gianpiero Tamburrini, Kristin M Conway, James E. Boggan, and Janine M. LaSalle
Subjects: Proband, Linkage disequilibrium, Genotype, Bone Morphogenetic Protein 7, Genome-wide association study, Single-nucleotide polymorphism, Biology, genome‑wide association study, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Craniosynostosis, Paediatrics and Reproductive Medicine, 03 medical and health sciences, single nucleotide polymorphisms, Craniosynostoses, Complementary and Alternative Medicine, non syndromic craniosynostosis, Genes, Reporter, Risk Factors, Genetics, medicine, GWAS, Settore BIO/13 - BIOLOGIA APPLICATA, Humans, Genetic Predisposition to Disease, Promoter Regions, Genetic, Genetics (clinical), Alleles, 030304 developmental biology, PCDH11X, Genetics & Heredity, 0303 health sciences, 030305 genetics & heredity, Genetic Variation, Odds ratio, DNA Methylation, medicine.disease, Introns, craniosynostosis, Imputation (genetics), Genome-Wide Association Study
Abstract: Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10(−8)): rs781716 (P = 4.71 × 10(−9); odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10(−8); OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10(−9); OR = 0.34), located ~155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10(−8), OR = 0.45; P = 3.31 × 10(−8), OR = 0.45; P = 1.09 × 10(−8), OR=0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10(−8), OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10(−6)). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821–55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.
Published: 2020

17. GATAD2B-associated neurodevelopmental disorder (GAND) : clinical and molecular insights into a NuRD-related disorder

Author: Lisa Ohden, Jenny Morton, M. J. Hajianpour, Geoffrey Beek, Rebecca C. Spillmann, Donald Basel, Christine Shieh, Joel P. Mackay, Richard S. Finkel, Stanley F. Nelson, Andrew Choi, Shane McKee, Thomas D. Challman, Karen E. Wain, Loren D M Pena, Rosemarie Smith, David R. FitzPatrick, Natasha Jones, John M. Graham, Brigitte Vanle, Samantha A. Vergano, Kay Metcalfe, Julian A. Martinez, Ana Berta Sousa, Luis O Rohena, Usha Kini, Alden Y. Huang, Andrew Dauber, Maria Gabriela Otero, Karen W. Gripp, Mauricio R. Delgado, Roman Yusupov, Judith D. Ranells, Miranda Splitt, David Chitayat, Mary-Louise Freckmann, Juan I. Young, Emilie D. Douine, Eric D. Marsh, Helen Cox, Sunita Venkateswaran, Jane A. Hurst, Ingrid P. Taff, Margaret G. Au, Katheryn Grand, Laura Davis-Keppen, Hilary J. Vernon, Andrea H. Seeley, Tyler Mark Pierson, Hane Lee, Ana P. G. Silva, Katherine Lachlan, Sakkubai Naidu, Sonal Mahida, James J. Dowling, and Repositório da Universidade de Lisboa
Subjects: 0301 basic medicine, education, 030105 genetics & heredity, Biology, NuRD complex, GATA Transcription Factors, Article, Frameshift mutation, Chromatin remodeling, 03 medical and health sciences, GATAD2B, Neurodevelopmental disorder, Pregnancy, Apraxia of speech, Intellectual Disability, medicine, Missense mutation, Humans, Macrocephaly, Child, Genetics (clinical), Genetics, medicine.disease, Mi-2/NuRD complex, Human genetics, Hypotonia, Megalencephaly, Nucleosomes, Repressor Proteins, 030104 developmental biology, Phenotype, Neurodevelopmental Disorders, Female, medicine.symptom
Abstract: Copyright © 2020, American College of Medical Genetics and Genomics, Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). Methods: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. Results: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. Conclusions: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly., Research reported in this paper was supported by the National Institutes of Health (NIH) Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. GAND50’s seq+ analysis was supported by NIH National Center for Advancing Translational Science (NCATS) UCLA Clinical and Translational Science Institute (CTSI) grant number UL1TR001881. J.P.M. received funding from the National Health and Medical Research Council (APP1012161, APP1063301, APP1126357, APP1058916). T.M.P. and this research was supported by the Cedars-Sinai institutional funding program and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular and the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program. T.M.P. is especially grateful for the wonderful and continued support from the Cedars-Sinai Fashion Industries Guild.
Published: 2020

18. Quantifying the contribution of recessive coding variation to developmental disorders

Author: Nadia Akawi, James Stephenson, Jeffrey C. Barrett, Rebecca E. McIntyre, Hilary C. Martin, Sebastian S. Gerety, Matthew E. Hurles, Carla P. Jones, Diana S. Johnson, John Dean, Sarju G. Mehta, Elena Prigmore, Meena Balasubramanian, Rachel Horton, Michael Wright, Giuseppe Gallone, Mari Niemi, Miranda Splitt, Peter D. Turnpenny, Mark Sanderson, Dhavendra Kumar, Caroline F. Wright, Wendy D Jones, Pradeep C. Vasudevan, Andrew R. Bassett, Juliet Handsaker, Katie Johnson, Joanna Kaplanis, Alice Hulbert, Michaela Bruntraeger, Elizabeth J. Radford, Jenny Morton, Michael J. Parker, Helen V. Firth, Gabriela Sánchez-Andrade, Patrick J. Short, David R. FitzPatrick, Jeremy F. McRae, and Sally Ann Lynch
Subjects: 0301 basic medicine, Jumonji Domain-Containing Histone Demethylases, genetic structures, Developmental Disabilities, Eukaryotic Initiation Factor-3, Genes, Recessive, Penetrance, Genome-wide association study, Biology, Article, Mice, 03 medical and health sciences, Phylogenetics, Genetic variation, Animals, Humans, Pakistan, In patient, Gene, Phylogeny, Genetics, Multidisciplinary, Genetic Variation, Nuclear Proteins, Genetic code, eye diseases, Europe, Repressor Proteins, Disease Models, Animal, 030104 developmental biology, Genetic Code, Genome-Wide Association Study, Coding (social sciences)
Abstract: Genetic architecture of developmental disorders The genetics of developmental disorders (DDs) is complex. Martin et al. wanted to determine the degree of recessive inheritance of DDs in protein-coding genes. They examined the exomes of more than 6000 families in populations with high and low proportions of consanguineous marriages. They found that 3.6% of DDs in individuals of European ancestry involved recessive coding disorders, less than a tenth of the levels previously estimated. Furthermore, among South Asians with high parental relatedness, rather than most of the disorders arising from inherited variants, fewer than half had a recessive coding diagnosis. Science , this issue p. 1161
Published: 2018
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19. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Author: Naomi Meeks, Stefan Kindler, Anya Revah-Politi, Alexander P.A. Stegmann, Vinodh Narayanan, Dominique Bonneau, Claudia Schob, Jill A. Rosenfeld, Jennifer E. Posey, Tim M. Strom, LaDonna Immken, Tjitske Kleefstra, Jolanda H. Schieving, Katherine L. Helbig, Estelle Colin, Magalie Barth, Tamar Harel, Matthew J. Huentelman, James R. Lupski, Benjamin Cogné, Han G. Brunner, Yaping Yang, Sébastien Küry, Jenny Morton, Erica H. Gerkes, Keri Ramsey, Marine Tessarech, Zeynep Coban-Akdemir, Shimon Edvardson, Hans-Jürgen Kreienkamp, Nelly Oundjian, Davor Lessel, Christian Kubisch, Thomas Besnard, Jonas Denecke, Orly Elpeleg, Ana M. Claasen, Kelsey Zegar, Mohammad K. Eldomery, Sandra Mercier, Margot R.F. Reijnders, Stéphane Bézieau, Univ Angers, Okina, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Central Nervous System, Male, DISRUPTION, INTELLECTUAL DISABILITY, Developmental Disabilities, PROTEIN, DISEASE, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, Global developmental delay, Amino Acids, Child, Genetics (clinical), Genetics, Adenosine Triphosphatases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Translation (biology), Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, FAMILY, Child, Preschool, Female, RNA Helicases, MODULE, Adolescent, Mutation, Missense, RNA GRANULES, Biology, Article, Cell Line, 03 medical and health sciences, Stress granule, Cell Line, Tumor, medicine, Humans, HELICASE, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], STRESS GRANULES, Helicase, RNA, Correction, medicine.disease, GENE, 030104 developmental biology, HEK293 Cells, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Contains fulltext : 182457.pdf (Publisher’s version ) (Open Access) DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.
Published: 2017
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20. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Author: Asbjørg Stray-Pedersen, Anne Ronan, Yunru Shao, Eric Haan, Katharina Steindl, Zöe Powis, Perla Thulin, Giuseppe Testa, Janneke H M Schuurs-Hoeijmakers, William J. Craigen, Raman Kumar, David Rodriguez-Buritica, Michele Gabriele, Laura S. Farach, Susanne Kjaergaard, Rolph Pfundt, Jillian Nicholl, Jozef Gecz, Petter Strømme, Stefan H. Lelieveld, Kenjiro Kosaki, Sally Ann Lynch, Kimberly M. Nugent, Willy M. Nillesen, Bregje W.M. van Bon, Jill A. Rosenfeld, Charlotte Brasch-Andersen, Eirik Frengen, Lisenka E.L.M. Vissers, Scott D. McLean, Evelyn Douglas, Joris Andrieux, David A. Koolen, Anneke T. Vulto-van Silfhout, Han G. Brunner, Arie van Haeringen, Jenny Morton, Sophie Patrier, Anita Rauch, Christeen Ramane J. Pedurupillay, Pierre-Luc Germain, Peter J. Anderson, Christian Gilissen, Christian P. Schaaf, Alessandro Vitriolo, Jennifer Friedman, Toshiki Takenouchi, Pascal Chambon, Bert B.A. de Vries, Doriana Misceo, Pernille Mathiesen Tørring, Family Medicine, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: FHML non-thematic output
Subjects: Male, Models, Molecular, 0301 basic medicine, Transcription, Genetic, Haploinsufficiency, Cohort Studies, Histones, 0302 clinical medicine, Missense mutation, Lymphocytes, YY1 Transcription Factor, Genetics (clinical), GENE-EXPRESSION, Genetics, KANSL1 CAUSE, Acetylation, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], DEMETHYLASE JMJD3, Chromatin, Enhancer Elements, Genetic, Child, Preschool, embryonic structures, Female, Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7], STEM-CELLS, Protein Binding, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Chromatin Immunoprecipitation, LIQUID WATER, Adolescent, Mutation, Missense, Repressor, Biology, Methylation, Article, 17Q21.31 MICRODELETION SYNDROME, 03 medical and health sciences, ADENOVIRUS E1A, Protein Domains, Intellectual Disability, Journal Article, Humans, Enhancer, Transcription factor, Hemizygote, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, POTENTIAL FUNCTIONS, Activator (genetics), YY1, MUTATIONS, Gene Ontology, 030104 developmental biology, Haplotypes, 030217 neurology & neurosurgery, MENTAL-RETARDATION
Abstract: Contains fulltext : 174704.pdf (Publisher’s version ) (Open Access) Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.
Published: 2017
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21. The Influence of Epigenetic Factors in Four Pairs of Twins With Non-Syndromic Craniosynostosis

Author: Mark S. Lloyd, Jenny Morton, Saadia Farooq, and Sandhya Trichinopoly Krishna
Subjects: Male, Pediatrics, medicine.medical_specialty, Health Status, Twins, Craniosynostosis, Epigenesis, Genetic, 03 medical and health sciences, Craniosynostoses, 0302 clinical medicine, Breech presentation, Pregnancy, medicine, Humans, 030223 otorhinolaryngology, Retrospective Studies, Fibrous joint, business.industry, Smoking, Infant, Retrospective cohort study, 030206 dentistry, General Medicine, medicine.disease, Twin study, medicine.anatomical_structure, Otorhinolaryngology, Developmental Milestone, Surgery, Female, Presentation (obstetrics), business
Abstract: The aims of this retrospective case series were to investigate whether twins born with craniosynostosis mirrored each other regarding operative surgery performed, age of undertaking surgery; outcomes in speech, language, and developmental milestones and what environmental factors were present for each set of twins.Case selection was based on clinical and radiographical evidence of craniosynostosis amongst twin sets. The twin sets included were those with craniosynostosis who had different sutures affected or those with the same suture affected but with a varying degree of severity.The presence of the following factors may have played an influential role in the clinical presentation of the twins; these were as follows: a maternal history of smoking, breech presentation, and genetic mutations. It was notable that the overall outcomes for the twins in this study were similar.These cases highlight the multifactorial nature in the development of craniosynostosis and how this influenced the phenotypic presentation of the twins.
Published: 2019

22. Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review

Author: Neeti Ghali, Vinod Varghese, Frances Gibbon, Andrew E. Fry, Andrew G. L. Douglas, Meena Balasubramanian, Catharina (Nienke) M.L. Volker-Touw, Sally Ann Lynch, Mayy El Gamal, Michael Parker, Anna Durkin, Katherine Lachlan, Denise Williams, Alice Gardham, Volker Straub, Ruth Newbury-Ecob, Virginia Clowes, Ana Beleza, Shadi Albaba, Jenny Morton, Natalie Canham, and Peter D Turnpenny
Subjects: 0301 basic medicine, Proband, Male, Pediatrics, medicine.medical_specialty, Microcephaly, Adolescent, Haploinsufficiency, Heterogeneous-Nuclear Ribonucleoprotein U, 030105 genetics & heredity, Craniofacial Abnormalities, 03 medical and health sciences, Pregnancy, Seizures, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Craniofacial, Child, Genetics (clinical), Exome sequencing, Genetic testing, medicine.diagnostic_test, business.industry, Brain, Infant, Syndrome, medicine.disease, 030104 developmental biology, Palpebral fissure, Neurodevelopmental Disorders, Child, Preschool, Female, business
Abstract: With advances in genetic testing and improved access to such advances, whole exome sequencing is becoming a first-line investigation in clinical work-up of children with developmental delay/intellectual disability (ID). As a result, the need to understand the importance of genetic variants and its effect on the clinical phenotype is increasing. Here, we report on the largest cohort of patients with HNRNPU variants. These 21 patients follow on from the previous study published by Yates et al. in 2017 from our group predominantly identified from the Deciphering Developmental Disorders study that reported seven patients with HNRNPU variants. All the probands reported here have a de novo loss-of-function variant. These probands have craniofacial dysmorphic features, in the majority including widely spaced teeth, microcephaly, high arched eyebrows, and palpebral fissure abnormalities. Many of the patients in the group also have moderate to severe ID and seizures that tend to start in early childhood. This series has allowed us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency, and expand substantially on already published literature on HNRNPU-related neurodevelopmental syndrome.
Published: 2019

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

Author: Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Published: 2019
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24. Biallelic mutations inCYP26B1: A differential diagnosis for Pfeiffer and Antley-Bixler syndromes

Author: Sophia Frentz, Jenny Morton, Stephen P. Robertson, Andrew J. Sutherland-Smith, and Timothy R. Morgan
Subjects: Models, Molecular, 0301 basic medicine, Pathology, medicine.medical_specialty, Protein Conformation, Acrocephalosyndactylia, DNA Mutational Analysis, 030105 genetics & heredity, Biology, Oligodactyly, Craniosynostosis, Diagnosis, Differential, Young Adult, 03 medical and health sciences, Genetics, medicine, Humans, Missense mutation, Alleles, Genetics (clinical), Homozygote, Skull, Facies, Anatomy, Retinoic Acid 4-Hydroxylase, Synostosis, medicine.disease, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Amino Acid Substitution, Dysplasia, Mutation, Female, Tomography, X-Ray Computed, Antley-Bixler Syndrome Phenotype
Abstract: Recently, a newly identified autosomal recessive skeletal dysplasia was described characterized by calvarial abnormalities (including cranium bifidum, coronal, and lambdoid synostosis), oligodactyly, femoral bowing, narrow thorax, small pelvic bones, and radiohumeral synostosis. In the two families described, a more severe phenotype led to in utero lethality in three siblings while in a single patient in a second family the phenotype was sufficiently mild to allow survival to 5 months of age. The disorder is caused by biallelic missense mutations in CYP26B1, which encodes for a cytochrome P450 enzyme responsible for the catabolism of retinoic acid in a temporally and spatially restricted fashion during embryonic development. Here, we provide the third family affected by the disorder and the first affected individual to survive beyond infancy. This woman homozygous for c.1303G>A; p.(Gly435Ser) in CYP26B1, which was associated with multisutural synostosis, radiohumeral synostosis, normal bone mineral density, and apparent intellectual disability, a phenotype with significant similarities to Antley-Bixler and Pfeiffer syndromes. © 2016 Wiley Periodicals, Inc.
Published: 2016
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25. Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype

Author: Josh Willoughby, Jenny Morton, Meena Balasubramanian, Francis H. Sansbury, Julie Vogt, Elizabeth A. Jones, Rory O'Sullivan, Jill Clayton-Smith, Sarah E. Turton, Helen Cox, Nicola S. Cooper, Katherine Lachlan, Julia Rankin, Frances Elmslie, Jessica A. Radley, and Sarah F. Smithson
Subjects: 0301 basic medicine, Male, Microcephaly, Pediatrics, medicine.medical_specialty, Germline mosaicism, 030105 genetics & heredity, 03 medical and health sciences, Epilepsy, Intellectual disability, Exome Sequencing, Genetics, medicine, Guanine Nucleotide Exchange Factors, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), Alleles, Genetic Association Studies, business.industry, Facies, Genetic Variation, Infant, Twins, Monozygotic, medicine.disease, Hypotonia, 030104 developmental biology, Phenotype, Amino Acid Substitution, Child, Preschool, Autism, Female, medicine.symptom, business, Brachycephaly, Developmental regression
Abstract: Whole-exome sequencing has established IQSEC2 as a neurodevelopmental disability gene. The IQSEC2 variant phenotype includes developmental delay, intellectual disability, epilepsy, hypotonia, autism, developmental regression, microcephaly and stereotypies but is yet to be fully described. Presented here are 14 new patients with IQSEC2 variants. In addition to the established features, we observed: gait ataxia in 7 of 9 (77.8%), drooling in 9 of 14 (64.2%), early feeding difficulties in 7 of 14 (50%), structural brain abnormalities in 6 of 13 (46.2%), brachycephaly in 5 of 14 (35.7%), and scoliosis and paroxysms of laughter each in 4 of 14 (28.6%). We suggest that these are features of the IQSEC2-related disorder. Gastrostomy requirement, plagiocephaly, strabismus and cortical blindness, each seen in 2 of 14 (14.3%), may also be associated. Shared facial features were noted in 8 of 14 patients, and shared hair patterning was identified in 5 of 14 patients. This study further delineates the IQSEC2 phenotypic spectrum and supports the notion of an emerging IQSEC2 syndrome. We draw parallels between the IQSEC2-related disorder and the Angelman-/Rett-/Pitt-Hopkins syndrome group of conditions and recommend the addition of IQSEC2 to epilepsy and developmental delay gene panels. We observed discordant phenotypes in monozygotic twins and apparent gonadal mosaicism, which has implications for recurrence risk counselling in the IQSEC2-related disorder.
Published: 2018

26. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018
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27. Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection

Author: Basil Paul, Yong Xu, Guo-Lian Ding, Yan Kong, Ddd study, Qi Wu, Xinguo Hou, Wenjun Zhou, Atteeq U. Rehman, Sungguan Hong, Yanlin He, John Dean, Wenxian Zhou, Zhandong Liu, Pengfei Liu, Chuhan Wang, Zheng Sun, Emmanuel Scalais, Hari Krishna Yalamanchili, Ying-Wooi Wan, Mary O'Driscoll, Hao Liu, Jenny Morton, Yingyun Gong, and Qingchun Tong
Subjects: 0301 basic medicine, Lateral hypothalamus, Databases, Factual, Hypothalamus, Mice, Transgenic, Hippocampal formation, Biology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Memory, Intellectual Disability, Neural Pathways, medicine, Animals, Nuclear Receptor Co-Repressor 1, Nuclear Receptor Co-Repressor 2, GABAergic Neurons, Nuclear receptor co-repressor 1, Memory Disorders, Neuronal Plasticity, GABAA receptor, General Neuroscience, Excitatory Postsynaptic Potentials, Long-term potentiation, Receptors, GABA-A, CA3 Region, Hippocampal, 030104 developmental biology, medicine.anatomical_structure, nervous system, Synaptic plasticity, GABAergic, Neuron, Neuroscience, 030217 neurology & neurosurgery
Abstract: Nuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus-hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.
Published: 2018

28. Mutations in the BAF-complex subunit DPF2 associated with Coffin-Siris syndrome

Author: Andrew O.M. Wilkie, Georgia Vasileiou, Bernt Popp, Yun Li, Maren Wenzel, Marion Gérard, Susan Tomkins, Jenny Morton, Megan T. Cho, André Reis, Astrid Weber, George E. Hoganson, Beate Albrecht, Felix B. Engel, Arif B. Ekici, Maria-Renée Plona, Janine Altmüller, Christian Thiel, Christian Büttner, Jill Clayton-Smith, Karen Low, Dagmar Wieczorek, Deciphering Developmental Disorders Study, Bernd Wollnik, Eduardo Calpena, Nuria C. Bramswig, Sabine Endele, Hermann-Josef Lüdecke, Silvia Vergarajauregui, Tim M. Strom, Institute of Human Genetics, University Erlangen-Nuremberg, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Institut für Humangenetik, Regional Genetic Service, St Mary's Hospital, Manchester, West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), University Medicine Goettingen, Department of Pediatrics [Chicago, IL, USA] (College of Medicine), University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, GeneDx [Gaithersburg, MD, USA], JRC Institute for Energy and Transport (IET), European Commission - Joint Research Centre [Petten], Institut für Humangenetik [Essen], Universitätsklinikum Essen, Technical University of Munich (TUM), Institute of Human Genetics, University Hospital Erlangen, Institute of Human Genetics [Erlangen, Allemagne], Université de Lorraine (UL), Institute of Human Genetics [Cologne], Universitätsklinikum Köln (Uniklinik Köln)-University of Cologne, University Medical Center Göttingen (UMG), Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Technische Universität München [München] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Birmingham Women's and Children's NHS Foundation Trust, University Hospitals Bristol, Liverpool Women's NHS Foundation Trust, Genetikum, Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Illinois College of Medicine, University of Illinois System, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Male, Medizin, PHD finger, MESH: Amino Acid Sequence, Histones, 0302 clinical medicine, MESH: Child, Chlorocebus aethiops, MESH: Hand Deformities, Congenital, Missense mutation, Coffin-Siris syndrome, histone modification, MESH: Animals, BAF complex, nuclear aggregates, Child, Genetics (clinical), Genetics, MESH: Histones, MESH: Protein Subunits, DNA-Binding Proteins, MESH: COS Cells, Histone, Phenotype, DPF2, MESH: Facies, intellectual disability, Child, Preschool, MESH: HEK293 Cells, COS Cells, Female, MESH: Neck, Hand Deformities, Congenital, MESH: Face, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, Protein subunit, Micrognathism, dominant negative, autism spectrum disorder, Biology, MESH: Micrognathism, MESH: Phenotype, Frameshift mutation, MESH: Intellectual Disability, 03 medical and health sciences, Report, medicine, Animals, Humans, Abnormalities, Multiple, Amino Acid Sequence, Gene, Coffin–Siris syndrome, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Coarse facial features, MESH: Child, Preschool, Facies, medicine.disease, MESH: Cercopithecus aethiops, MESH: Male, Protein Subunits, Autism Spectrum Disorder, Baf Complex, Coffin-siris Syndrome, Dominant Negative, Dpf2, Histone Modification, Intellectual Disability, Nail Hypoplasia, Nuclear Aggregates, Phd Finger, 030104 developmental biology, HEK293 Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, Mutation, biology.protein, nail hypoplasia, MESH: Female, 030217 neurology & neurosurgery, Neck, MESH: DNA-Binding Proteins, Transcription Factors
Abstract: International audience; Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.
Published: 2018
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29. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

Author: Olivier Vanakker, Maria Kirchhoff, Christian Gilissen, Jenny Morton, Ineke van der Burgt, Kelly Radtke, Tugce Aktas, Sarah Vergult, Diana Johnson, Tobias Rumpf, Tony Roscioli, André Reis, Alan Fryer, Salima El Chehadeh, Christel Thauvin-Robinet, Ange Line Bruel, Rolph Pfundt, Sander Pajusalu, David Francis, Asifa Akhtar, Iben Bache, Tiong Yang Tan, Vera M. Kalscheuer, Meredith Wilson, Björn Menten, Giuseppe Semplicio, Julien Thevenon, Richard Fisher, Yannis Duffourd, Gerhard Mittler, Witold G. Szymanski, M. Felicia Basilicata, Victoria McKay, Kristin Lindstrom, Han G. Brunner, Katrin Õunap, Jaya Ganesh, Claudia Isabelle Keller Valsecchi, Megan T. Cho, Laurence Faivre, MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Max-Planck-Gesellschaft, 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), 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), FHU TRANSLAD (CHU de Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Copenhagen University Hospitals, Radboud University Medical Center [Nijmegen], Center for Medical Genetics [Ghent], Ghent University Hospital, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], GeneDx [Gaithersburg, MD, USA], Murdoch Children's Research Institute (MCRI), Department of Clinical Genetics [Copenhagen], Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Sheffield Children's NHS Foundation Trust, Liverpool Women's NHS Foundation Trust, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: Male, 0301 basic medicine, CHROMATIN, INTELLECTUAL DISABILITY, Chromosomal Proteins, Non-Histone, CHROMOSOME, Cohort Studies, Histones, Mice, Genes, X-Linked, MSL complex, Child, Cells, Cultured, Histone Acetyltransferases, Epigenomics, Acetylation, Genetic Diseases, X-Linked, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Chromatin, Cell biology, DNA-Binding Proteins, DROSOPHILA, Histone, ACETYLTRANSFERASE, Child, Preschool, Female, Adolescent, Mice, Transgenic, Biology, Article, Histone H4, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Genetics, Animals, Humans, CELL-CYCLE, Epigenetics, DEACETYLASE, MOF, MSL3, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DOSAGE COMPENSATION COMPLEX, Infant, Dosage compensation complex, PROTEIN INTERACTIONS, HEK293 Cells, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Case-Control Studies, Mutation, biology.protein, Histone deacetylase, Protein Processing, Post-Translational, Transcription Factors, Ultra-rare developmental disorders
Abstract: International audience; The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.
Published: 2018
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30. A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history

Author: Adnan Y. Manzur, Jacek Pilch, Neeti Ghali, Jahannaz Dastgir, Diana Johnson, Cecilia Giunta, Nayana Lahiri, Anthony Vandersteen, Uschi Lindert, Christine Fauth, Angela F. Brady, Rebecca C. Pollitt, Bernarda Lozić, Gudrun Schreiber, Ebtesam M. Abdalla, Nora Shannon, Martina Witsch-Baumgartner, Glenda Sobey, Ariana Kariminejad, F. Michael Pope, James J. Collins, Marianne Rohrbach, Jenny Morton, Sandra Donkervoort, Johannes Koch, Johannes Zschocke, Fleur S van Dijk, Carsten G. Bönnemann, Marius E. Kraenzlin, Matthias Baumann, University of Zurich, and Giunta, Cecilia
Subjects: Male, 0301 basic medicine, Joint hypermobility, medicine.medical_specialty, Pathology, 2716 Genetics (clinical), Hearing loss, DNA Mutational Analysis, Connective tissue, 610 Medicine & health, Biology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Molecular genetics, FKBP22, medicine, Humans, Original Research Article, Child, Myopathy, Alleles, Genetic Association Studies, Genetics (clinical), kyphoscoliotic Ehlers-Danlos syndrome, Chromosome Mapping, Peptidylprolyl Isomerase, mutations, medicine.disease, diagnostic criteria, FKBP14, FKBP22, kyphoscoliotic Ehlers-Danlos syndrome, mutations, Magnetic Resonance Imaging, Natural history, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Ehlers–Danlos syndrome, 10036 Medical Clinic, FKBP14, Child, Preschool, diagnostic criteria, Mutation, Cohort, Ehlers-Danlos Syndrome, Female, medicine.symptom, Magnetic Resonance Angiography, 030217 neurology & neurosurgery
Abstract: Purpose\ud In 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.\ud \ud Methods\ud We report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.\ud \ud Results\ud Based on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.\ud \ud Conclusion\ud Our data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS.
Published: 2018

31. Genotype-phenotype correlation in NF1 : evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844–848

Author: Elizabeth Siqveland, Concepción Hernández-Chico, Jonathan Zonana, Melissa Crenshaw, Maurice J. Mahoney, Eric Legius, Helene Verhelst, Débora Romeo Bertola, Karen W. Gripp, Tom Callens, Jaishri O. Blakeley, Nicole J. Ullrich, Arelis Martir-Negron, Karol Rubin, Marica Eoli, Margaret R. Wallace, Jose Guevara-Campos, Karin Dahan, Zhenbin Chen, Patricia Galvin-Parton, Elaine H. Zackai, Isabelle Maystadt, Radhika Dhamija, Lane S. Rutledge, Meriel McEntagart, Rick van Minkelen, Geert Mortier, Meena Balasubramanian, La Donna Immken, Maria Daniela D'Agostino, Anne Destree, Alicia Gomes, Kenneth N. Rosenbaum, Rhonda L. Schonberg, Emma Burkitt-Wright, Meng-Chang Hsiao, Meena Upadhyaya, Sherrell Johnson, Meredith Seidel, Alessandro De Luca, Troy A. Becker, David T. Miller, Veronica Saletti, Bruce R. Korf, Shay Ben-Shachar, Carey McDougall, David W. Stockton, Magdalena Koczkowska, Kathleen Claes, Laura Russell, Ludwine Messiaen, D. Gareth Evans, Mitch Cunningham, Allison Schreiber, Scott R. Plotkin, Dinel A. Pond, Kristi J. Jones, Vickie Zurcher, Jaya K. George-Abraham, Alison Callaway, Beth Keena, Yunjia Chen, Neil A. Hanchard, Angela Sharp, Yoon Sim Yap, Karin Soares Gonçalves Cunha, Nancy J. Mendelsohn, Jenny Morton, Christopher P. Barnett, Yolanda Martin, Aaina Kochhar, Eva Trevisson, Jan Liebelt, John Pappas, Sandra Janssens, and Clinical Genetics
Subjects: 0301 basic medicine, Proband, Male, Cohort Studies, codons 844–848, Medicine and Health Sciences, Missense mutation, CSRD, Child, Genetics (clinical), Neurofibromatosis type I, Genetics, education.field_of_study, NEUROFIBROMATOSIS TYPE-I, Neurofibromin 1, Genetic disorder, Phenotype, NERVE SHEATH TUMORS, Female, codons 844-848, Heterozygote, congenital, hereditary, and neonatal diseases and abnormalities, spinal NF, Neurofibromatosis 1, VONRECKLINGHAUSEN NEUROFIBROMATOSIS, Adolescent, Genetic counseling, Population, Mutation, Missense, NOONAN-SYNDROME, Spinal neurofibromas, genotype-phenotype correlation, neurofibromatosis type 1, Article, 03 medical and health sciences, Young Adult, MPNST, missense mutation, NF1, plexiform neurofibroma, medicine, Humans, Computer Simulation, Amino Acid Sequence, OPTIC PATHWAY GLIOMAS, Neurofibromatosis, education, Codon, Genetic Association Studies, Demography, SPINAL NEUROFIBROMATOSIS, business.industry, Biology and Life Sciences, NATURAL-HISTORY, SOUTH EAST WALES, medicine.disease, 030104 developmental biology, TYPE-1 NEUROFIBROMATOSIS, Human medicine, business, PLEXIFORM NEUROFIBROMAS
Abstract: Neurofibromatosis type 1 (NF1), one of the most common genetic disorders with an estimated prevalence of 1:3000 live births, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and an in-frame 1-amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 patients (129 unrelated probands and 33 affected relatives) carrying a constitutional missense mutation affecting one of five neighboring NF1 codons Leu844, Cys845, Ala846, Leu847 and Gly848, located in the Cysteine-Serine-Rich Domain (CSRD). These recurrent missense mutations affect ~0.8% of unrelated NF1 mutation-positive probands in the UAB cohort. A substantial fraction of these patients presented with a severe phenotype, including plexiform and/or spinal neurofibromas, symptomatic optic pathway gliomas, malignant neoplasms or osseous lesions. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent compared with classic NF1 cohorts (both p
Published: 2018
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32. Genetics of learning disability

Author: Alison Foster, Hannah Titheradge, and Jenny Morton
Subjects: Genetics, medicine.medical_specialty, Fragile x, business.industry, Genetic counseling, education, Single gene, medicine.disease, Optimal management, Pediatrics, Perinatology and Child Health, Learning disability, Intellectual disability, medicine, Copy-number variation, medicine.symptom, Psychiatry, business
Abstract: A significant proportion of children with learning disability will have an underlying genetic cause. The genetic aetiology of learning disability is broad and includes chromosomal abnormalities, copy number variants, single gene, mitochondrial and imprinting disorders. New genetic technologies are increasing the likelihood that a diagnosis will be made in a child with a learning disability. This provides information on prognosis and complications, thereby facilitating optimal management for the child and genetic counselling for the family. Here we provide an overview of the genetics of learning disability and a clinical approach to investigating a child with a learning disability. The clinical features and management of a number of specific genetic conditions of particular relevance to paediatricians are described.
Published: 2015
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33. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

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

Author: Sally Ann Lynch, Pradeep C. Vasudevan, Wendy D Jones, Hilary C. Martin, John Dean, James Stephenson, Sarju G. Mehta, Elena Prigmore, Katie Johnson, Michael Parker, Patrick J. Short, Jenny Morton, Mari Niemi, Miranda Splitt, Matthew E. Hurles, Rachel Horton, Joanna Kaplanis, Michael Wright, David R. FitzPatrick, Jeremy F. McRae, Elizabeth J. Radford, Diana Johnson, Jeffrey C. Barrett, Alice Hulbert, Caroline F. Wright, Juliet Handsaker, Meena Balasubramanian, Peter D. Turnpenny, Giuseppe Gallone, Dhavendra Kumar, Nadia Akawi, and Helen V. Firth
Subjects: Disease gene, Genetics, 0303 health sciences, Biology, Compound heterozygosity, Penetrance, 3. Good health, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Bonferroni correction, New disease, Genotype, symbols, Polygenic risk score, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained by de novo coding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction: EIF3F, KDM5B, and THOC6. EIF3F is a novel disease gene, and KDM5B has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.
Published: 2017
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35. Further Evidence for Dlgap2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene

Author: Helene Poquet, Laurence Faivre, Salima El Chehadeh, Jenny Morton, Dominic McMullan, Susan Hamilton, Himanshu Goel, Bertrand Isidor, Cedric Le Caignec, Joris Andrieux, Bruno Delobel, Eva Pipiras, Anne Claude Tabet, Andree Delahaye, Loic Depontual, Mathilde Lefebvre, Caroline Jacquot, Alice Masurel, Frederic Huet, Jean Michel Pinoit, Vincent Meille, Maud Benetti, Eddy Ponavoy, Jean Christophe Chauvet Gelinier, Benoit Trojak, Bernard Bonin, Christine Juif, Anne Collinet de la Salle, Christel Thauvin Robinet, Nathalie Lagarde, Celine Henry, Nathalie Marle, Patrick Callier, and Anne Laure Mosca Boidron
Subjects: 0301 basic medicine, medicine.medical_specialty, Candidate gene, medicine.disease, Glutamatergic postsynaptic density, Penetrance, 03 medical and health sciences, 030104 developmental biology, Autism spectrum disorder, mental disorders, Intellectual disability, medicine, General Earth and Planetary Sciences, Autism, Specific Learning Disorder, Copy-number variation, Psychiatry, Psychology, General Environmental Science
Abstract: Autism spectrum disorders are classified as neurodevelopmental disorders characterised by diminished social communication and interaction. The core symptoms typically coexist with other medical conditions such as intellectual disability. The involvement of rare copy number variations of varying expressivity and penetrance as risk factors in autism spectrum disorders/intellectual disability phenotypes has been highlighted in large series. The DLGAP2 gene, whose glutamatergic postsynaptic density product may play a role in synaptogenesis and plasticity, has been identified as a novel candidate on the basis of 2 de novo duplications in sporadic non-syndromic autism spectrum disorders/intellectual disability males. It has also been suggested that increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia spectrum disorders. Based on these results and after fine phenotyping of another patient with a de novo duplication involving DLGAP2 and presenting with autism spectrum disorder intersecting early-onset schizophrenia spectrum disorder, we gathered an international series of 9 cases (6 families) via international data sharing. Four sporadic males presented with autism spectrum disorders and one had other neurodevelopmental disorders. A family with 4 females displayed intellectual disability (2/4) and specific learning disorder (2/4). This study supports the hypothesis that rare copy number variations encompassing DLGAP2 with incomplete penetrance and variable expressivity could predispose to a broad range of early-onset neurodevelopmental disorders trajectories including autism spectrum disorders/intellectual disability, highlighting the existence of common predisposing factors to these overlapping phenotypic spectrums.
Published: 2017
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36. 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
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37. Author Correction: Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus–CA3 projection

Author: Zhandong Liu, Jenny Morton, Qingchun Tong, Wenxian Zhou, Yong Xu, Zheng Sun, Yan Kong, Hao Liu, Atteeq U. Rehman, Emmanuel Scalais, Yingyun Gong, Ddd study, Chuhan Wang, Basil Paul, Guo-Lian Ding, Hari Krishna Yalamanchili, Wenjun Zhou, Xinguo Hou, Yanlin He, Qi Wu, Ying-Wooi Wan, Mary O'Driscoll, John Dean, Sungguan Hong, and Pengfei Liu
Subjects: American diabetes association, Scholarship, General Neuroscience, Published Erratum, Library science, Psychology, Neuroscience, Sentence
Abstract: In the version of this article initially published, the Acknowledgements erroneously included a grant number that did not directly support the work in the article. The last sentence of the Acknowledgments should have read, "The authors' laboratories were supported by National Natural Science Foundation of China grants 31671222 and 31571556 (G.D.), a Taishan Scholarship (X.H.), the American Diabetes Association (ADA1-17-PDF-138) (Y.H.), the US Department of Agriculture (USDA) Cris6250-51000-059-04S (Y.X.), National Institutes of Health grants R01DK101379, R01DK117281, P01DK113954, R01DK115761 (Y.X.), the American Heart Association grant AHA30970064 (Z.S.), and grants R21CA215591 and R01ES027544 (Z.S.)." The error has been corrected in the HTML and PDF versions of the article.
Published: 2019
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38. Clinical and molecular consequences of disease-associated de novo mutations in SATB2

Author: Hemant, Bengani, Mark, Handley, Mohsan, Alvi, Rita, Ibitoye, Melissa, Lees, Sally Ann, Lynch, Wayne, Lam, Madeleine, Fannemel, Ann, Nordgren, H, Malmgren, M, Kvarnung, Sarju, Mehta, Shane, McKee, Margo, Whiteford, Fiona, Stewart, Fiona, Connell, Jill, Clayton-Smith, Sahar, Mansour, Shehla, Mohammed, Alan, Fryer, Jenny, Morton, Detelina, Grozeva, Tara, Asam, David, Moore, Alejandro, Sifrim, Jeremy, McRae, Matthew E, Hurles, Helen V, Firth, F Lucy, Raymond, Usha, Kini, Christoffer, Nellåker, Ddd Study, and David R, FitzPatrick
Subjects: CUT domain, Whole Genome Sequencing, Mutation, Missense, absent speech, Haploinsufficiency, Matrix Attachment Region Binding Proteins, de novo mutation, Cell Line, Cohort Studies, SATB2, Loss of Function Mutation, intellectual disability, Humans, Original Research Article, Genetic Association Studies, HeLa Cells, Protein Binding, Transcription Factors
Abstract: Purpose: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability. Methods: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production. Subcellular localization and mobility of wild-type and mutant SATB2 were assessed using fluorescently tagged protein. Results: Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19). Six of eight missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA-binding domains. SATB2 nuclear mobility was mutation-dependent; p.Arg389Cys in CUT1 increased mobility and both p.Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in individuals with missense variants were indistinguishable from those with loss of function. Conclusion: SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. When mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association. Genet Med advance online publication 02 February 2017
Published: 2016

39. BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

Author: Gabriela Sánchez-Andrade, Susan E. Holder, Jeremy F. McRae, Stephen J. Sawiak, Song-Choon Lee, Pelagia Deriziotis, Shelagh Joss, Tjitske Kleefstra, Julien Thevenon, Jenny Morton, Simon E. Fisher, Cristina Dias, Mathew E. Hurles, Sara Busquets Estruch, Kelly Mellul, Claire L. S. Turner, Darren W. Logan, Sarah A. Graham, Rui Santos, Ximena Ibarra-Soria, Laurence Faivre, Jane A. Hurst, Pentao Liu, DDD Study, Biologie moléculaire et cellulaire de la différenciation, Université Joseph Fourier - Grenoble 1 (UJF)-Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 849 Department of Human Genetics, Radboud University Medical Center [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, The Wellcome Trust Sanger Institute [Cambridge], and Max Planck Society University of Cambridge Wellcome Trust EMBO Health Innovation Challenge Fund HICF-1009-003 Department of Health Wellcome Trust Sanger Institute National Institute for Health Research through the Comprehensive Clinical Research Network Regional Council of Burgundy Dijon University Hospital
Subjects: 0301 basic medicine, Male, Haploinsufficiency/genetics, Microcephaly, Transcription, Genetic, Codon, Nonsense/genetics, Haploinsufficiency, Neurodevelopmental Disorders/genetics, Hippocampus, projection neurons, neural development, Microcephaly/genetics, Mice, 0302 clinical medicine, Intellectual disability, epileptic encephalopathies, Missense mutation, Genetics(clinical), genes, Frameshift Mutation, Genetics (clinical), Genetics, Cerebral Cortex, axon guidance, 2p15p16.1 microdeletion syndrome, Nuclear Proteins, cell-differentiation, Syndrome, Transcription Factors/chemistry, Phenotype, Mutation, Missense/genetics, Codon, Nonsense, Neuroinformatics, lymphoid development, autism spectrum disorders, Hippocampus/metabolism, Mutation, Missense, Nuclear Proteins/chemistry, Biology, Article, Frameshift mutation, 03 medical and health sciences, Intellectual Disability, medicine, Animals, Humans, Social Behavior, Transcription factor, Frameshift Mutation/genetics, Loss function, de-novo mutations, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic heterogeneity, Chromatin Assembly and Disassembly/genetics, Carrier Proteins/chemistry, medicine.disease, Chromatin Assembly and Disassembly, Intellectual Disability/genetics, Repressor Proteins, 030104 developmental biology, Cerebral Cortex/metabolism, Neurodevelopmental Disorders, Carrier Proteins, Cognition Disorders, Transcriptome, Cognition Disorders/genetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Contains fulltext : 167380.pdf (Publisher’s version ) (Open Access) Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes. 22 p.
Published: 2016
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40. Mandibulofacial Dysostosis with Microcephaly:Mutation and Database Update

Author: Jenny Morton, Francine Pinheiro Favaro, Deborah J. Shears, Fabiola Quintero-Rivera, Art Grix, Shelagh Joss, Margaret H. Harr, Antonie D. Kline, William B. Dobyns, Vanesa López-González, Josh Silver, John C. Johnson, I. Karen Temple, Angela E. Scheuerle, Julie Lauzon, Jane Estrella, Amanda C. Smith, Himanshu Goel, Elaine H. Zackai, Judith Allanson, Ghayda M. Mirzaa, Matthew Osmond, Kym M. Boycott, Julie Richer, Taila Hartley, Matthew A. Lines, Laura A. Baker, Alasdair G. W. Hunter, Usha Kini, Johanna Martinezmoles, Louise C. Pyle, Cindy Hudson, Hanna Faghfoury, Susan M. White, Jiddeke M. van de Kamp, Megan R. Vanstone, Dorte L Lildballe, Dennis E. Bulman, Chantal F. Morel, Bitten Schönewolf-Greulich, Tabib Dabir, Cliff J Meldrum, Nick Barrowman, Maria Leine Guion-Almeida, Katrina M. Dipple, Ruobing Zou, Fleur S van Dijk, Lijia Huang, Pernille Axel Gregersen, Anthony Vandersteen, Amy S. Kimball, and Karen W. Gripp
Subjects: Models, Molecular, 0301 basic medicine, Microcephaly, RNA Splicing, Amino Acid Motifs, Molecular Sequence Data, Gene Expression, Penetrance, Germline mosaicism, Haploinsufficiency, Choanal atresia, Mandibulofacial dysostosis with microcephaly, Biology, Mandibulofacial dysostosis, computer.software_genre, Protein Structure, Secondary, Article, EFTUD2, 03 medical and health sciences, Intellectual Disability, Databases, Genetic, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, Craniofacial, Hearing Loss, MFDM, Ribonucleoprotein, U5 Small Nuclear, Genetics (clinical), Mandibulofacial dysostosis Guion-Almeida type, Database, Peptide Elongation Factors, medicine.disease, Protein Structure, Tertiary, Phenotype, 030104 developmental biology, Mutation, Spliceosomes, computer, Treacher Collins syndrome, Mandibulofacial Dysostosis
Abstract: Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).
Published: 2016
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41. Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders

Author: Susan J Hinze, Christopher P. Barnett, Ching Moey, Cheryl Shoubridge, Jozef Gecz, Jillian Nicholl, Nicola Brunetti-Pierri, Louise Brueton, Jenny Morton, Dominic J. McMullan, Benjamin Kamien, Moey, Ching, Hinze, Susan J., Brueton, Louise, Morton, Jenny, Mcmullan, Dominic J., Kamien, Benjamin, Barnett, Christopher P., BRUNETTI PIERRI, Nicola, Nicholl, Jillian, Gecz, Jozef, and Shoubridge, Cheryl
Subjects: 0301 basic medicine, Male, Adolescent, Chromosomal Proteins, Non-Histone, Cell Cycle Proteins, Disease, SMC1A, Biology, Bioinformatics, Article, 03 medical and health sciences, Young Adult, Intellectual Disability, Intellectual disability, Gene duplication, Chromosome Duplication, medicine, Genetics, Guanine Nucleotide Exchange Factors, Humans, Copy-number variation, RNA, Messenger, Young adult, Child, Gene, Genetics (clinical), Regulation of gene expression, Histone Demethylases, Behavior, Chromosomes, Human, X, Infant, Newborn, Infant, Nuclear Proteins, medicine.disease, Pedigree, DNA-Binding Proteins, 030104 developmental biology, Gene Expression Regulation, Neurodevelopmental Disorders, Child, Preschool, Female
Abstract: Copy number variations are a common cause of intellectual disability (ID). Determining the contribution of copy number variants (CNVs), particularly gains, to disease remains challenging. Here, we report four males with ID with sub-microscopic duplications at Xp11.2 and review the few cases with overlapping duplications reported to date. We established the extent of the duplicated regions in each case encompassing a minimum of three known disease genes TSPYL2, KDM5C and IQSEC2 with one case also duplicating the known disease gene HUWE1. Patients with a duplication encompassing TSPYL2, KDM5C and IQSEC2 without gains of nearby SMC1A and HUWE1 genes have not been reported thus far. All cases presented with ID and significant deficits of speech development. Some patients also manifested behavioral disturbances such as hyperactivity and attention-deficit/hyperactivity disorder. Lymphoblastic cell lines from patients show markedly elevated levels of TSPYL2, KDM5C and SMC1A, transcripts consistent with the extent of their CNVs. The duplicated region in our patients contains several genes known to escape X-inactivation, including KDM5C, IQSEC2 and SMC1A. In silico analysis of expression data in selected gene expression omnibus series indicates that dosage of these genes, especially IQSEC2, is similar in males and females despite the fact they escape from X-inactivation in females. Taken together, the data suggest that gains in Xp11.22 including IQSEC2 cause ID and are associated with hyperactivity and attention-deficit/hyperactivity disorder, and are likely to be dosage-sensitive in males.
Published: 2016

42. Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis

Author: Ian Young, Sara MacKay, Klaus Zerres, Jenny Morton, Fabio De Leonardis, Lihadh Al-Gazali, Beyhan Tüysüz, Céline Huber, Geert Mortier, Antonio Rossi, Arnold Munnich, Erkan Koparir, Julie Désir, Mathilde Nizon, Yasemin Alanay, Mélanie Fradin, Martine Le Merrer, Antonella Forlino, Valérie Cormier-Daire, Carine Le Goff, Rodolphe Merrina, Catheline Vilain, Bassam Abu-Libdeh, Jill Clayton-Smith, Sarenur Basaran, Marie T. Greally, Beate Albrecht, Harinder Gill, David Sillence, Merel C van Maarle, Acibadem University Dspace, and Human Genetics
Subjects: Joint Instability, Spondyloepiphyseal dysplasia, Sulfotransferase, CHST3, Dwarfism, Biology, medicine.disease_cause, Craniofacial Abnormalities, Nucleotidases, proteoglycan metabolism, Genetics, medicine, Humans, CANT1, Glycosides, Gene, Cells, Cultured, Research Articles, Genetics (clinical), Mutation, Polydactyly, Ossification, Ossification, Heterotopic, medicine.disease, Phenotype, Chromatography, Gel, Proteoglycans, Human medicine, Sulfotransferases, medicine.symptom, Desbuquois dysplasia type 1 and type 2
Abstract: Desbuquois dysplasia (DD) is characterized by antenatal and postnatal short stature, multiple dislocations, and advanced carpal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. We have identified mutations in calcium activated nucleotidase 1 gene (CANT1) in DD type 1. Recently, CANT1 mutations have been reported in the Kim variant of DD, characterized by short metacarpals and elongated phalanges. DD has overlapping features with spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) due to Carbohydrate (chondroitin 6) Sulfotransferase 3 (CHST3) mutations. We screened CANT1 and CHST3 in 38 DD cases (6 type 1 patients, 1 Kim variant, and 31 type 2 patients) and found CANT1 mutations in all DD type 1 cases, the Kim variant and in one atypical DD type 2 expanding the clinical spectrum of hand anomalies observed with CANT1 mutations. We also identified in one DD type 2 case CHST3 mutation supporting the phenotype overlap with SDCD. To further define function of CANT1, we studied proteoglycan synthesis in CANT1 mutated patient fibroblasts, and found significant reduced GAG synthesis in presence of beta-D-xyloside, suggesting that CANT1 plays a role in proteoglycan metabolism. Hum Mutat 33:1261-1266, 2012. (c) 2012 Wiley Periodicals, Inc.
Published: 2012
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43. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

Author: Sixto García-Miñaur, Ratna Veeramachaneni, Susan Price, Nicola Ragge, Kay Metcalfe, Graeme C.M. Black, Christopher P. Bennett, William Reardon, Alex Magee, Soo Mi Park, Jill Clayton-Smith, Nicole Revencu, Bruce Castle, Christine Oley, Wayne W.K. Lam, Vivienne McConnell, Deirdre E. Donnelly, Deepthi De Silva, Andrew E. Fry, I. Karen Temple, Judith A. Goodship, Helen Kingston, Gunnar Houge, Fiona Stewart, Sally J. Davies, Frances Elmslie, John Tolmie, Sancha Bunstone, Harinder Gill, Emma Howard, Shehla Mohammed, Moira Blyth, Michael Parker, Emma Hobson, Dian Donnai, Michael Wright, Kate Chandler, Amanda L. Collins, Susann Schweiger, Katherine Lachlan, Alex Henderson, Richard Gibbons, Siren Berland, Audrey Smith, Sally Ann Lynch, Pradeep Vasudevan, Bronwyn Kerr, Richard Fisher, Meriel McEntagart, Jenny Morton, Siddharth Banka, Yanick J. Crow, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, and UCL - (SLuc) Centre de génétique médicale UCL
Subjects: Biology, medicine.disease_cause, Article, Cohort Studies, Genetic Heterogeneity, Exon, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, Epigenetics, Genetics (clinical), Mutation, Genetic heterogeneity, Cancer, Sequence Analysis, DNA, medicine.disease, Hematologic Diseases, Phenotype, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, Face, Female, Kabuki syndrome
Abstract: MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients. © 2012 Macmillan Publishers Limited All rights reserved.
Published: 2011
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44. Is the party over: Ecstasy

Author: Jenny Morton
Subjects: medicine.medical_specialty, Ecstasy, medicine, Psychiatry, Psychology, General Biochemistry, Genetics and Molecular Biology
Abstract: To a generation of partygoers, Ecstasy [3,4methylenedioxymethamphetamine (MDMA)] represents one of the safest illegal drugs available and, superficially, evidence supports this notion. Compared with other recreational drugs, there have been relatively few Ecstasyrelated deaths and there is little direct evidence for shortterm neurotoxicity at recreational doses. However, Ecstasy causes 5hydroxytryptamine (5HT) nerveterminal damage in rats, mice and monkeys, and, in several studies, the damage is irreversible.
Published: 2007
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45. Cerebro-costo-mandibular syndrome: Clinical, radiological, and genetic findings

Author: Francois P. Bernier, Sarah F. Smithson, Danielle C. Lynch, C Wallis, Debbie Shears, Jenny Morton, Elaine H. Zackai, Melissa Lees, Amaka C. Offiah, Usha Kini, Angela Barnicoat, Nobue Itasaki, Emma Wakeling, Tom Hilliard, Jillian S. Parboosingh, Jill Clayton-Smith, Alistair Calder, Simon Langton-Hewer, Angus John Clarke, Rebecca Hewitson, Elizabeth J. Bhoj, Richard H Scott, Madeleine J. Tooley, Michael Saunders, Tessa Homfray, Moira Blyth, and Peter Davis
Subjects: 0301 basic medicine, Male, Microcephaly, Pathology, medicine.medical_specialty, Adolescent, Micrognathism, Ribs, Scoliosis, 030105 genetics & heredity, snRNP Core Proteins, 03 medical and health sciences, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Craniofacial, Child, Genetics (clinical), Rib cage, Respiratory distress, business.industry, Hyoid bone, Horseshoe kidney, Infant, Exons, medicine.disease, Cleft Palate, 030104 developmental biology, Child, Preschool, Mutation, Pierre Robin syndrome, Spliceosomes, Female, business
Abstract: Cerebro-Costo-Mandibular syndrome (CCMS) is a rare autosomal dominant condition comprising branchial arch-derivative malformations with striking rib-gaps. Affected patients often have respiratory difficulties, associated with upper airway obstruction, reduced thoracic capacity, and scoliosis. We describe a series of 12 sporadic and 4 familial patients including 13 infants/children and 3 adults. Severe micrognathia and reduced numbers of ribs with gaps are consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis are common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defect may occur. Microcephaly and significant developmental delay are present in a small minority of patients. Key radiological findings are of a narrow thorax, multiple posterior rib gaps and abnormal costo-transverse articulation. A novel finding in 2 patients is bilateral accessory ossicles arising from the hyoid bone. Recently, specific mutations in SNRPB, which encodes components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. DNA was available from 14 patients and SNRPB mutations were identified in 12 (4 previously reported). Eleven had recurrent mutations previously described in patients with CCMS and one had a novel mutation in the alternative exon. These results confirm the specificity of SNRPB mutations in CCMS and provide further evidence for the role of spliceosomal proteins in craniofacial and thoracic development.
Published: 2015

46. Genetic Heterogeneity and Clinical Variability in Musculocontractural Ehlers-Danlos Syndrome Caused by Impaired Dermatan Sulfate Biosynthesis

Author: Ingrid Hausser, Jenny Morton, Merel C. Maiburg, Ingrid M.B.H. van de Laar, Delfien Syx, Tim Van Damme, Sofie Symoens, Anne De Paepe, Miguel del Campo, Trinh Hermanns-Lê, Fransiska Malfait, Mohnish Suri, and Clinical Genetics
Subjects: Male, Decorin, Biopsy, Iduronic acid, DSE, Case Reports, Review, EDS, chemistry.chemical_compound, Genetics(clinical), Non-U.S. Gov't, Child, Genetics (clinical), Skin, Medicine(all), Dermatan sulfate epimerase-1, Research Support, Non-U.S. Gov't, Exons, Extracellular Matrix, Neoplasm Proteins, Pedigree, DNA-Binding Proteins, medicine.anatomical_structure, Phenotype, Biochemistry, Female, Collagen, CHST14, Sulfotransferases, Adult, medicine.medical_specialty, Adolescent, Molecular Sequence Data, Connective tissue, Dermatan Sulfate, Biology, Research Support, Dermatan sulfate, Genetic Heterogeneity, Young Adult, Antigens, Neoplasm, Internal medicine, medicine, Genetics, Journal Article, Humans, Chondroitin sulfate, Amino Acid Sequence, RNA, Messenger, Genetic heterogeneity, Facies, medicine.disease, Dermatan 4-O-sulfotransferase-1, Fibronectins, carbohydrates (lipids), Endocrinology, chemistry, Proteoglycan, Ehlers–Danlos syndrome, Mutation, biology.protein, Ehlers-Danlos Syndrome, Ehlers-Danlos syndrome, Sequence Alignment
Abstract: Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.
Published: 2015

47. Characterization of Human Disease Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

Author: Marlène Rio, Vincent Laugel, Christine Barnerias, Vijay Aswani, Guillermo Agosta, Rachel Straussberg, Diana Chase, Maja Di Rocco, Mohamed S. Abdel-Hamid, Daniel R. Carvalho, Montse Arellano, Maya Thomas, Yanick J. Crow, Giovanni Crichiutti, Lyvia Dabydeen, Miriam Bloom, Kathryn J. Swoboda, Bertrand Isidor, Kevin J. Murray, Nasaim Khan, Agathe Roubertie, Kathryn Bailey, Johanna Lowenstein Schmidt, Noemi Nunez-Enamorado, Venkateswaran Ramesh, Simona Orcesi, Michael C Fahey, Keng Wee Teik, Ram L. Kumar, Gabriella Forte, Roberta Battini, Alec Aeby, Flore Rozenberg, Nadia Bahi-Buisson, Eileen Baildam, Sam Ackroyd, Magnhild Rasmussen, Doriette Soler, Diana Rodriguez, Marjo S. van der Knaap, Sheela Nampoothiri, Bülent Kara, Ivana Olivieri, Julie Vogt, Julie S. Prendiville, Ghada M H Abdel-Salam, Thierry Billette de Villemeur, Ronen Spiegel, Tommy Stödberg, Rudy Van Coster, Marianne Till, Alberto B. Burlina, Enza Maria Valente, Patrick J. Oades, Gyanranjan P. Sinha, Beverley Anderson, William P Whitehouse, Raymon Vijzelaar, Liesbeth De Waele, Cristina Cereda, Hannah J. Webb, Gillian I. Rice, Geneviève Bernard, Anthony Oojageer, Stefano D'Arrigo, Ming K. Lim, Donncha Hanrahan, Nuno Cordeiro, Adeline Vanderver, Hannah Gornall, Manuel Castro-Gago, Johann te Water Naude, Grace Vassallo, Stavit Allon-Shalev, Belén Pérez-Dueñas, Charles Marques Lourenço, Sameer M. Zuberi, Magalie Barth, Lieven Lagae, Cyril Goizet, Christian de Goede, Tiong Yang Tan, Jenny Morton, Riyana Babul-Hirji, Mark T Mackay, Geoffrey Wallace, Elisabetta Salvatici, Heinz Lauffer, Corinne De Laet, Federica Ricci, Russell C. Dale, Maria Luisa Carpanelli, Catherine Albin, Elisa Fazzi, Michael W. Beresford, Pierre Lebon, Abigail Collins, Roberta La Piana, Amy Pizzino, Edward Blair, Nirmala Rani Gowrinathan, Mohnish Suri, Rima Nabbout, Guy Helman, Luc Régal, Karin Segers, John H. Livingston, Davide Tonduti, Uta Tacke, António Figueiredo, Robyn Whitney, Blanca Gener, John R. Østergaard, David Chitayat, Kalpana Gowrishankar, Tarja Linnankivi, Edwin P. Kirk, Jean-Pierre Lin, Pierre Landrieu, Isabella Moroni, Mary D. King, Colin D. Ferrie, Koenraad Devriendt, Anna Cavallini, Shane McKee, Marika Bianchi, Daphna Marom, Marcin Szynkiewicz, Isabelle Desguerre, Evangeline Wassmer, Kate Chandler, Maha S. Zaki, Inés Denzler, Giada Ariaudo, Marie Laure Moutard, Concepcion Sierra Corcoles, Pediatric surgery, NCA - Brain mechanisms in health and disease, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, and Other departments
Subjects: Interferon-Induced Helicase, IFIH1, Adenosine Deaminase, Autoimmune diseases, Fenótipo, Disease, Aicardi–Goutieres syndrome, Aicardi-Goutières syndrome, Bilateral striatal necrosis, DEAD-box RNA Helicases, 0302 clinical medicine, Genetics (clinical), 0303 health sciences, Doenças auto-imunes do sistema nervoso, 3. Good health, Phenotype, Spastic paraparesis, Biomarker (medicine), Vasculitis, bilateral striatal necrosis, spastic paraparesis, type I interferon, interferon signature, Genotype, Encephalopathy, Ribonuclease H, Alpha interferon, Biology, Nervous System Malformations, Article, SAM Domain and HD Domain-Containing Protein 1, 03 medical and health sciences, Autoimmune Diseases of the Nervous System, SDG 3 - Good Health and Well-being, Interferon signature, Type I interferon, Exodeoxyribonucleases, Genetic Association Studies, Humans, Interferons, Monomeric GTP-Binding Proteins, Phosphoproteins, Pterins, Mutation, Genetics, medicine, Chilblains, 030304 developmental biology, Aicardi-Goutieres syndromebilateral striatal necrosisspastic paraparesistype I interferoninterferon signature, medicine.disease, Peripheral neuropathy, Immunology, Aicardi–Goutières syndrome, 030217 neurology & neurosurgery
Abstract: Aicardi-Goutieres syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutieres syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. (c) 2015 Wiley Periodicals, Inc
Published: 2015
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48. Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor (BDNF) Gene

Author: John R. Hodges, Anna-Lynne R. Adlam, Areeg El Gharbawy, Jenny Morton, I. Sadaf Farooqi, Joan C. Han, Y. C. Loraine Tung, Giles S.H. Yeo, Stephen O'Rahilly, Jack A. Yanovski, Juliette Gray, F. Lucy Raymond, James J. Cox, and Julia M. Keogh
Subjects: Adult, Chromosomes, Artificial, Bacterial, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Hyperkinesis, Hyperphagia, medicine.disease_cause, Article, Energy homeostasis, Neurotrophic factors, Internal medicine, Diabetes mellitus, Internal Medicine, Humans, Medicine, Obesity, Chromosome Aberrations, Brain-derived neurotrophic factor, Mutation, biology, business.industry, Brain-Derived Neurotrophic Factor, Cognitive disorder, DNA, medicine.disease, Endocrinology, nervous system, Chromosome Inversion, biology.protein, Female, Cognition Disorders, business, Haploinsufficiency, Neurotrophin
Abstract: The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5′ end of the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.
Published: 2006
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49. The origin of EFNB1 mutations in craniofrontonasal syndrome: Frequent somatic mosaicism and explanation of the paucity of carrier males

Author: Indira B. Taylor, Anne Goriely, Andrew O.M. Wilkie, Irene M.J. Mathijssen, A. Jeannette M. Hoogeboom, Jenny Morton, Richard B. Fisher, Louise C. Wilson, Elizabeth Sweeney, Alexa Kidd, John B. Mulliken, M. Teresa Lourenço, Steven A. Wall, Kazuya Matsumoto, Stephen R.F. Twigg, Han G. Brunner, Clinical Genetics, and Plastic and Reconstructive Surgery and Hand Surgery
Subjects: Male, Heterozygote, Genetics and epigenetic pathways of disease [NCMLS 6], Genetic counseling, Germline mosaicism, Ephrin-B1, Biology, medicine.disease_cause, Germline, Craniofacial Abnormalities, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Germline mutation, Genetics, medicine, Humans, Genetics(clinical), Hypertelorism, Allele, Frontonasal dysplasia, 10. No inequality, Germ-Line Mutation, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, Mosaicism, 030305 genetics & heredity, Articles, medicine.disease, Pedigree, Genetic defects of metabolism [UMCN 5.1], Female, medicine.symptom
Abstract: Contains fulltext : 51037.pdf (Publisher’s version ) (Closed access) Craniofrontonasal syndrome (CFNS) is an X-linked disorder that exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis, and additional minor malformations, but males are usually mildly affected with hypertelorism only. Despite this, males appear underrepresented in CFNS pedigrees, with carrier males encountered infrequently compared with affected females. To investigate these unusual genetic features of CFNS, we exploited the recent discovery of causative mutations in the EFNB1 gene, which encodes ephrin-B1, to survey the molecular alterations in 59 families (39 newly investigated and 20 published elsewhere). We identified the first complete deletions of EFNB1, catalogued 27 novel intragenic mutations, and used Pyrosequencing and analysis of nearby polymorphic alleles to quantify mosaic cases and to determine the parental origin of verified germline mutations. Somatic mosaicism was demonstrated in 6 of 53 informative families, and, of 17 germline mutations in individuals for whom the parental origin of mutation could be demonstrated, 15 arose from the father. We conclude that the major factor accounting for the relative scarcity of carrier males is the bias toward mutations in the paternal germline (which present as affected female offspring) combined with reduced reproductive fitness in affected females. Postzygotic mutations also contribute to the female preponderance, whereas true nonpenetrance in males who are hemizygous for an EFNB1 mutation appears unusual. These results highlight the importance of considering possible origins of mutation in the counseling of families with CFNS and provide a generally applicable approach to the combined analysis of mosaic and germline mutations.
Published: 2006
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50. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux

Author: Nancy Braverman, Ling Yu Shih, Lihadh Al-Gazali, Hulya Bukulmez, Trevor Cole, Jeremy Kirk, Valérie Cormier-Daire, David Chitayat, Matthew L. Warman, Pius S. Padayatti, Melissa Lees, Geert Mortier, Chong Ae Kim, Laurence Faivre, Focco van den Akker, Jenny Morton, Conny M. A. van Ravenswaaij-Arts, David K. Rhee, Jules G. Leroy, Stefan Mundlos, Sarina G. Kant, Richard M. Pauli, Cynthia F. Bartels, Bernhard Zabel, and Yanick J. Crow
Subjects: Adult, Male, Protein Folding, medicine.medical_specialty, medicine.drug_class, Nonsense mutation, Dwarfism, Biology, medicine.disease_cause, Bone and Bones, Frameshift mutation, Internal medicine, Genetics, medicine, Natriuretic peptide, Humans, Missense mutation, Genetics(clinical), Abnormalities, Multiple, Receptor, Genetics (clinical), Bone Diseases, Developmental, Mutation, Cell Membrane, Articles, NPR2, Endochondral bone growth, Endocrinology, Genetic defects of metabolism [UMCN 5.1], Guanylate Cyclase, Case-Control Studies, Female, Receptors, Atrial Natriuretic Factor, Protein Binding
Abstract: Item does not contain fulltext The homodimeric transmembrane receptor natriuretic peptide receptor B (NPR-B [also known as guanylate cyclase B, GC-B, and GUC2B]; gene name NPR2) produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligand, C-type natriuretic peptide (CNP). CNP has previously been implicated in the regulation of skeletal growth in transgenic and knockout mice. The autosomal recessive skeletal dysplasia known as "acromesomelic dysplasia, type Maroteaux" (AMDM) maps to an interval that contains NPR2. We sequenced DNA from 21 families affected by AMDM and found 4 nonsense mutations, 4 frameshift mutations, 2 splice-site mutations, and 11 missense mutations. Molecular modeling was used to examine the putative protein change brought about by each missense mutation. Three missense mutations were tested in a functional assay and were found to have markedly deficient guanylyl cyclase activity. We also found that obligate carriers of NPR2 mutations have heights that are below the mean for matched controls. We conclude that, although NPR-B is expressed in a number of tissues, its major role is in the regulation of skeletal growth.
Published: 2004

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