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1. Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

Author

Newell Belnap, Bert B.A. de Vries, Austin Larson, Rolph Pfundt, Marijke R. Wevers, Valérie Benoit, Markus Zweier, Pascal Joset, Anita Rauch, Angela Bahr, Jeroen Mourmans, Patricia G Wheeler, Or Gozani, Marisa V. Andrews, Monica H. Wojcik, Didier Lacombe, Sarah Grotto, Marwan Shinawi, Lot Snijders Blok, Conny M. A. van Ravenswaaij-Arts, Keri Ramsey, Deepanwita Sengupta, Mariarosaria Lang-Muritano, Isabelle Maystadt, Katharina Steindl, Paolo Zanoni, Antonio Vitobello, Geoffroy Delplancq, Katrin Õunap, Tania Attié-Bitach, Heinrich Sticht, Giulia Petrilli, Laurence Faivre, Vassilis Tsatsaris, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
0301 basic medicine, In silico, Biology, Article, REGION, 03 medical and health sciences, ROGERS-DANKS-SYNDROME, 0302 clinical medicine, Missense mutation, HISTONE H3, Gene, Genetics (clinical), Loss function, Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DELETION, DEFECTS, Methylation, Phenotype, LYSINE 36, 030104 developmental biology, Molecular mechanism, WOLF-HIRSCHHORN-SYNDROME, 030217 neurology & neurosurgery, Function (biology), Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype., Genetics in Medicine, 23 (8)

Published
2021
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2. A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome

Author

Ann Seman, Rixa Woitschach, Duygu Selcen, Divya Nair, Lauren Gunderson, Mahim Jain, Sha Tang, Giuseppe Zampino, Julien L. Marcadier, Marielle Alders, Jason Pinner, Melanie Napier, Linda Hasadsri, Marina Macchiaiolo, Alyssa Blesson, Pavel N. Pichurin, Joseph T. Alaimo, Arjan Bouman, Philippe M. Campeau, Catherine Karimov, Chitra Prasad, Anne Dieux-Coeslier, Nicole L. Bertsch, Bernd Wollnik, Janine Altmüller, Zöe Powis, Holly Dubbs, Tahsin Stefan Barakat, Gregory M. Cooper, Kristen J. Rasmussen, Perrine Brunelle, Patrick R. Blackburn, Erica D. Smith, Jeff M. Milunsky, Katja Kloth, E. Martina Bebin, Lot Snijders Blok, Knut Brockmann, Karin Weiss, Xilma R. Ortiz-Gonzalez, Danna Gal, Dong Li, Francesca Clementina Radio, Joan M. Stoler, Elaine H. Zackai, Jiddeke M. van de Kamp, Deepali N. Shinde, Huifang Yan, Thomas Smol, Alejandro Ferrer, Dagmar Weise, Baiba Lace, Deborah L. Renaud, Lauren E. Bartik, Beth Keena, Michelle L. Thompson, Carol J Saunders, Theodore G. Drivas, Elizabeth J. Bhoj, Eric T. Rush, Marco Tartaglia, Eric W. Klee, Margit Burmeister, Jingmin Wang, Jonas Denecke, Clinical genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, and Clinical Genetics

Subjects
Adult, Male, CHD3 variants, Genetic testing, Adolescent, Snijders Blok-Campeau syndrome, Developmental Disabilities, medicine.disease_cause, Pediatrics, Article, Chromodomain, Craniofacial Abnormalities, Catalytic Domain, Intellectual Disability, Genetics, medicine, Missense mutation, Humans, Child, Genetics (clinical), Mutation, medicine.diagnostic_test, biology, Significant difference, DNA Helicases, Helicase, Infant, Syndrome, Autism spectrum disorders, Phenotype, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Child, Preschool, Cohort, biology.protein, Female, Mi-2 Nucleosome Remodeling and Deacetylase Complex
Abstract

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

Published
2020
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3. Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

Author

Danielle J. Owen, David FitzPatrick, Nina Mann, Stuart B. Bauer, Ilona Krey, Heather C Mefford, Jacob Zyskind, Roger Fick, Ana C. Onuchic-Whitford, Floor A. M. Duijkers, Etienne Coyaud, Simon E. Fisher, Juliann M. Savatt, Richard P. Lifton, Isabel Ottlewski, Amelie T. van der Ven, Peter J. Hulick, Nancy Rodig, Michelle A. Baum, Marielle Alders, Elysa J. Marco, Konrad Platzer, Ghaleb Daouk, Hadas Ityel, Eva H. Brilstra, Ian A. Glass, Heiko Reutter, Adda L. Graham-Paquin, Makiko Nakayama, Michael A. J. Ferguson, Amy Kolb, Weining Lu, Florian Buerger, Prabha Senguttuvan, Marcia Ferguson, Ronen Schneider, Isabelle Thiffault, Hila Milo Rasouly, Verena Klämbt, Tobias Bartolomaeus, Evan Chen, Mao Youying, Amar J. Majmundar, Jia Rao, Carrie Costin, Dina Ahram, Ali G. Gharavi, Lot Snijders Blok, Avram Z. Traum, Franziska Kause, Konstantin Deutsch, Arianna Vino, Dervla M. Connaughton, Antonie D. Kline, Deborah R. Stein, Daanya Salmanullah, Maxime Bouchard, Estelle M.N. Laurent, Audrey Squire, Daniel G. MacArthur, Kristen M. Laricchia, Asaf Vivante, Thomas M. Kitzler, Jonathan St-Germain, Brian Raught, Heidi L. Rehm, Ellen van Binsbergen, Chen Han Wilfred Wu, Caroline M. Kolvenbach, Monkol Lek, Selvin Kumar, Jing Chen, Mustafa K. Khokha, Ankana Daga, Hong Xu, Andrew D. Sharrocks, N. V. Shcherbakova, Simone Sanna-Cherchi, Inna S. Povolotskaya, Tze Y Lim, Johanna M. Rieke, Katrina M. Dipple, Gabriel C. Dworschak, Michael J. Somers, Tobias Hermle, Stefan Kohl, Steve Seltzsam, Victoria Y. Voinova, Shirlee Shril, Ingrid M. Wentzensen, Daw Yang Hwang, Velibor Tasic, Shrikant Mane, Jonathan Marquez, Friedhelm Hildebrandt, Rufeng Dai, Paulien A Terhal, Loai A. Eid, Thomas D. Challman, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), University of Western Ontario (UWO), Fudan University [Shanghai], University of Manchester [Manchester], Yale University [New Haven], McGill University = Université McGill [Montréal, Canada], Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Health Network, University of Toronto, Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Radboud University Medical Center [Nijmegen], Brigham & Women’s Hospital [Boston] (BWH), Tel Aviv University (TAU), University of Amsterdam [Amsterdam] (UvA), Universität Leipzig, University Medical Center [Utrecht], Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), GeneDx [Gaithersburg, MD, USA], University of Akron, University of Washington [Seattle], William Harvey Research Institute, Barts and the London Medical School, University of Edinburgh, Mary Bridge Childrens Hospital [Tacoma, WA, USA], NorthShore University HealthSystem [Evanston, IL, USA], Institute of Child Health [Tamil Nadu, India] (Hospital for Children), Boston University [Boston] (BU), Cortica Healthcare [San Rafael, CA, USA], Moscow Medical Institute of Health Ministry [Moscow, Russia], Pirogov Russian National Research Medical University, Dr. Mehta's Hospitals [Tamil Nadu, India], Seattle Children’s Hospital, Children's Mercy Hospital [Kansas City], University of Missouri [Kansas City] (UMKC), University of Missouri System, Neuro Spinal Hospital [Dubai, UAE], University Children’s Hospital [Skopje, Macédoine], Columbia University [New York], University Hospital Bonn, Massachusetts General Hospital [Boston], Rockefeller University [New York], Yale School of Medicine [New Haven, Connecticut] (YSM), Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Radboud university [Nijmegen], Tel Aviv University [Tel Aviv], Universität Leipzig [Leipzig], Pirogov Russian National Research Medical University [Moscow, Russia], Yale University School of Medicine, INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, and SALZET, Michel

Subjects
0301 basic medicine, Male, Morpholino, Xenopus, 030232 urology & nephrology, Endogenous retrovirus, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], transcription regulator, Interactome, Epigenesis, Genetic, Morpholinos, Pathogenesis, ZNF198, Mice, 0302 clinical medicine, whole-exome sequencing, Child, Urinary Tract, Genetics (clinical), Exome sequencing, Genetics, Mice, Knockout, ZMYM2, genetic kidney disease, Forkhead Transcription Factors, FOXP1, 3. Good health, Pedigree, extra-renal features, DNA-Binding Proteins, Child, Preschool, Larva, syndromic CAKUT, Female, Protein Binding, Neuroinformatics, Heterozygote, Biology, Article, Amphibian Proteins, 03 medical and health sciences, Exome Sequencing, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Gene silencing, Animals, Humans, Family, Transcription factor, FIM, Infant, Repressor Proteins, 030104 developmental biology, genomic analysis, Case-Control Studies, Urogenital Abnormalities, congenital anomalies of the kidney and urinary tract, Mutation, Transcription Factors
Abstract

International audience; Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CA-KUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpho-lino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and cranio-facial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endoge-nous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

Published
2020
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4. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author

Christopher Cunniff, Laurence Faivre, Simon E. Fisher, Hester Y. Kroes, Catherine Au, Rolph Pfundt, Jacqueline Leonard, Ahmad N. Abou Tayoun, Kosuke Izumi, Katherine Bergstrom, Deepali N. Shinde, Pelagia Deriziotis, Saskia M. Maas, Marcello Niceta, Antonio Vitobello, Sha Tang, Hanka Venselaar, Christophe Philippe, Christian Gilissen, Tjitske Kleefstra, Marco Tartaglia, Helen V. Firth, Nobuhiko Okamoto, Laurens Wiel, Lot Snijders Blok, Naomichi Matsumoto, Maria Lisa Dentici, Han G. Brunner, Samuel W. Baker, Susan Tomkins, Augusta M. A. Lachmeijer, Simon Bodek, Alejandro D. Iglesias, Monica H. Wojcik, Katrin Õunap, Noriko Miyake, Koen L.I. van Gassen, Zöe Powis, The DDD Study, Human Genetics, ANS - Complex Trait Genetics, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine

Subjects
0301 basic medicine, Male, Protein Conformation, Sequence Homology, Language in Interaction, Transactivation, 0302 clinical medicine, Neurodevelopmental disorder, BINDING, Transcriptional regulation, Missense mutation, Genetics(clinical), speech/language disorder, BRET assay, Child, de novo variants, luciferase reporter, Genetics (clinical), Genetics, TRANSCRIPTIONAL REGULATION, POU3F3, FOXP2, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], POU3F2, SPEECH, Brain-1, intellectual disability, Female, Neuroinformatics, Transcriptional Activation, EXPRESSION, GENES, Genotype, PROTEINS, Biology, BRN-2, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Report, medicine, Humans, Amino Acid Sequence, Allele, Gene, Transcription factor, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], medicine.disease, 030104 developmental biology, Gene Expression Regulation, Neurodevelopmental Disorders, Mutation, POU Domain Factors, HOMODIMERIZATION, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery
Abstract

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

Published
2019

5. Mutation update for the SATB2 gene

Author

Paul R. Mark, Katherine A. Bosanko, Vikas Bhambhani, Steven Sparagana, Laurie S. Sadler, Aisling R. Caffrey, Sixto García-Miñaur, Marilyn C. Jones, Douglas M. Smith, Andrea H. Seeley, Ann Oostra, Donna M. Martin, Marieke F. van Dooren, Melissa Lees, Melanie A. Manning, Meena Balasubramanian, Adeline Vanderver, Valeria Orlando, Maria Lisa Dentici, Ariel Brautbar, Elizabeth Roeder, Dorothy K. Grange, Jennifer L. Fish, Ralitza H. Gavrilova, Lot Snijders Blok, Jane Maclean, Marcelo Vargas, Suzanne I. M. Alsters, Daniela Melis, Lesley Turner, Eliana Kovitch, Yuri A. Zarate, Sakkubai Naidu, Lucía Spangenberg, Jonathan A. Bernstein, Elizabeth Berry-Kravis, Mark H. Lipson, Hilde Van Esch, Maria Schwab, Víctor Raggio, Timothy James Maarup, Marc S. Williams, Jean P. Pfotenhauer, Rebecca O. Littlejohn, Bert Callewaert, Adnan Alsadah, Antonio Martinez-Monseny, Juvianee I. Estrada-Veras, Human genetics, and Clinical Genetics

Subjects
Premature Stop Codon, Male, Adolescent, genotype-phenotype correlation, Mutation, Missense, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, 03 medical and health sciences, whole exome sequencing, Neurodevelopmental disorder, All institutes and research themes of the Radboud University Medical Center, SATB2-associated syndrome, Genetics, medicine, Missense mutation, Coding region, Animals, Humans, Child, Gene, Genetics (clinical), Exome sequencing, Genetic Association Studies, 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 030305 genetics & heredity, SATB2, Matrix Attachment Region Binding Proteins, medicine.disease, Phenotype, pathogenic variants, Disease Models, Animal, Neurodevelopmental Disorders, Child, Preschool, Codon, Terminator, Female, Transcription Factors
Abstract

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

Published
2019
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6. Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development

Author

A. Micheil Innes, Iryna Lobach, Ashley L. Lennox, A. James Barkovich, Caroline Nava, Amy S. Kimball, Sébastien Küry, Julien Thevenon, Benjamin Cogné, Marie Vincent, Debra L. Silver, Bertrand Isidor, Alban Ziegler, Paul Kuentz, Delphine Héron, Kimberly A. Aldinger, Dusica Babovic-Vuksanovic, Elliott H. Sherr, Jens Bunt, Ching Moey, Brieana Fregeau, Lindsey Suit, Diana Rodriguez, Ghayda M. Mirzaa, Patrick R. Blackburn, Noriko Miyake, Cyril Mignot, Brian H.Y. Chung, Alexandra Afenjar, Lot Snijders Blok, Mathilde Nizon, Laurence Faivre, Ruiji Jiang, Nataliya Di Donato, Charles J. Sheehan, Christel Thauvin-Robinet, Boris Keren, Perrine Charles, Bethany L. Johnson-Kerner, Dominique Martin-Coignard, Suzanne DeBrosse, Eric W. Klee, Stéphane Bézieau, Linda J. Richards, Lydie Burglen, Stephen N. Floor, and William B. Dobyns

Subjects
Genetics, Pathogenesis, Germline mutation, Neurogenesis, Polymicrogyria, medicine, Missense mutation, Translation (biology), Biology, DDX3X, medicine.disease, RNA Helicase A
Abstract

De novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuronal generation and migration. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity and induce ectopic RNA-protein granules and aberrant translation in neural progenitors and neurons. Together, our study demonstrates novel mechanisms underlying DDX3X syndrome, and highlights roles for RNA-protein aggregates in the pathogenesis of neurodevelopmental disease.

Published
2018
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7. Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development

Author

Dominique Martin-Coignard, Sébastien Küry, Benjamin Cogné, Lot Snijders Blok, Patrick R. Blackburn, Mathilde Nizon, Diana Rodriguez, Ching Moey, Bethany L. Johnson-Kerner, Noriko Miyake, Philippe M. Campeau, Delphine Héron, Elliott H. Sherr, Nataliya Di Donato, Iryna Lobach, Dusica Babovic-Vuksanovic, Caroline Nava, Alexandra Afenjar, A. Micheil Innes, Ruiji Jiang, Naomichi Matsumoto, Stéphane Bézieau, Amy S. Kimball, Marie Vincent, Jens Bunt, Kimberly A. Aldinger, Christel Thauvin-Robinet, Julien Thevenon, Stephen N. Floor, Brian H.Y. Chung, Alban Ziegler, Maria Daniela D'Agostino, Ghayda M. Mirzaa, Paul Kuentz, Laurence Faivre, Cyril Mignot, William B. Dobyns, Boris Keren, Brieana Fregeau, Lindsey Suit, Lydie Burglen, Mariah L. Hoye, Atsushi Fujita, Debra L. Silver, Charles J. Sheehan, A. James Barkovich, Fernando C. Alsina, Srivats Venkataramanan, Bertrand Isidor, Perrine Charles, Eric W. Klee, Linda J. Richards, Ashley L. Lennox, and Cynthia J. Curry

Subjects
0301 basic medicine, Male, Neurogenesis, Mutation, Missense, Biology, Pathogenesis, DEAD-box RNA Helicases, 03 medical and health sciences, Mice, 0302 clinical medicine, Germline mutation, Stress granule, Cell Line, Tumor, Polymicrogyria, medicine, Missense mutation, Animals, Humans, Cells, Cultured, Genetics, Cerebral Cortex, General Neuroscience, medicine.disease, RNA Helicase A, Mice, Inbred C57BL, 030104 developmental biology, Neurodevelopmental Disorders, RNA, Female, DDX3X, 030217 neurology & neurosurgery
Abstract

Summary De novo germline mutations in the RNA helicase DDX3X account for 1%–3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.

Published
2018

8. NBEA : developmental disease gene with early generalized epilepsy phenotypes

Author

Hermine E. Veenstra-Knol, Rolph Pfundt, Nada Houcinat, Gregory M. Cooper, James J. Riviello, Frédéric Bilan, Servi J. C. Stevens, Susan M. Hiatt, Mary K. Kukolich, Anna Lehman, Brigitte Gilbert-Dussardier, Cédric Le Caignec, Christian Korff, Catharina M L Volker-Touw, Eva H. Brilstra, Louise Bier, Alexander P.A. Stegmann, Evan H. Baugh, Berten Ceulemans, David Goldstein, Magalie Barth, Heather C. Mefford, Elaine Pereira, Han G. Brunner, Lot Snijders Blok, E. Lopez-Rangel, Rob P.W. Rouhl, Anya Revah-Politi, Bertrand Isidor, Mathilde Pacault, Constance T. R. M. Stumpel, E. Martina Bebin, Dana Craiu, Aida Telegrafi, Marlies Kempers, Jolien Roovers, Erin L. Heinzen, Candace T. Meyers, D Barca, Tania Djémié, Nicholas Stong, Zsuzsanna Siegler, Maureen S. Mulhern, Johannes R. Lemke, Tristan T. Sands, Natalie Lippa, Nicolette S. den Hollander, Danielle McBrian, Ellen van Binsbergen, Sarah Weckhuysen, Mariëtte J.V. Hoffer, CAUSES Study, EuroEPINOMICS-RES-MAE Working Grp, MUMC+: DA KG Polikliniek (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Klinische Neurowetenschappen, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Neurologie (9), MUMC+: DA KG Lab Centraal Lab (9), Columbia University Medical Center (CUMC), Columbia University [New York], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Radboud University Medical Center [Nijmegen], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], GeneDx [Gaithersburg, MD, USA], 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), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Department of Human Genetics, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium, University of Antwerp (UA), University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève], Hôpitaux Universitaires de Genève (HUG), University Medical Center [Utrecht], Department of Medical Genetics, Department of Medicine, Karolinska Institutet [Stockholm], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Male, 0301 basic medicine, Carrier Proteins/genetics, Candidate gene, Disease, Neurodevelopmental Disorders/genetics, Epilepsy, 0302 clinical medicine, Nerve Tissue Proteins/genetics, Child, Atonic seizure, Genetics, ddc:618, Phenotype, Neurology, Child, Preschool, Epilepsy, Generalized, Female, NEUROBEACHIN, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adolescent, Genotype, Generalized/genetics, Nerve Tissue Proteins, Biology, PATIENT, Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, medicine, Journal Article, Humans, Generalized epilepsy, AUTISM, Preschool, Gene, SPECTRUM, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DELETION, NBEA encodes neurobeachin, medicine.disease, FRAMEWORK, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, DE-NOVO MUTATIONS, Mutation, Autism, Neurology (clinical), Human medicine, Carrier Proteins, 030217 neurology & neurosurgery
Abstract

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803

Published
2018
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9. De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Author

Richard E. Person, Victoria R. Sanders, Jeremy W. Prokop, Robert J. Hopkin, Rosemarie Smith, Simon E. Fisher, Kevin M. Bowling, Krysta L. Engel, Marleen Simon, Lot Snijders Blok, Amy Crunk, Rolph Pfundt, Xilma R. Ortiz-Gonzalez, Haley Streff, Katherine S. Elliott, Claudia A. L. Ruivenkamp, Jane A. Hurst, E. Martina Bebin, Michael F. Wangler, J. Nicholas Cochran, Gregory M. Cooper, Sameer M. Zuberi, Han G. Brunner, Joseph D. Symonds, Paulien A Terhal, Tjitske Kleefstra, Holly Dubbs, Abigail N. Masunga, Emilia K. Bijlsma, Susan M. Hiatt, Heather M. McLaughlin, The DDD study, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA Klinische Genetica (5)

Subjects
0301 basic medicine, MISSENSE MUTATIONS, Neuroinformatics, Adult, Male, Heart malformation, SYNDROMIC INTELLECTUAL DISABILITY, Mutation, Missense, Biology, DIAGNOSIS, Language in Interaction, 03 medical and health sciences, Neurodevelopmental disorder, All institutes and research themes of the Radboud University Medical Center, Intellectual disability, medicine, Genetics, Missense mutation, Humans, TRANSCRIPTION, Amino Acid Sequence, Child, Gene, Genetics (clinical), Transcription Initiation, Genetic, Sequence Deletion, Original Investigation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Mediator Complex, AUTISM SPECTRUM DISORDER, Ubiquitination, medicine.disease, MODULE ASSOCIATION, FRAMEWORK, Cyclin-Dependent Kinase 8, GENE, Human genetics, Hypotonia, United Kingdom, 3. Good health, PREVALENCE, 030104 developmental biology, Autism spectrum disorder, Neurodevelopmental Disorders, NEXT-GENERATION, Child, Preschool, Female, medicine.symptom
Abstract

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes. Electronic supplementary material The online version of this article (10.1007/s00439-018-1887-y) contains supplementary material, which is available to authorized users.

Published
2017

10. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Tjitske Kleefstra, Katherine G. Keating, Marie Shaw, Lisenka E.L.M. Vissers, Sascha Vermeer, Jane Juusola, Barbara K. Burton, Margaret H. Harr, Hanka Venselaar, Kevin A. Strauss, Angela Myers, Antonie D. Kline, Karlla W. Brigatti, Koen L.I. van Gassen, Wendy K. Chung, E. Smeets, Willemijn M. Wissink-Lindhout, Usha Kini, Katrina Tatton-Brown, Alexander Hoischen, Amy S. Kimball, C Jensen, Hilde Van Esch, Christian Gilissen, Maaike Vreeburg, Patrick Reed, Perciliz L. Tan, M Bienek, Diana Baralle, Julie McLaughlin, Joyce Fox, Stefan A. Haas, Nicholas Katsanis, Tom S. Koemans, Jolanda H. Schieving, Janneke H M Schuurs-Hoeijmakers, Jennifer Norman, Vera M. Kalscheuer, Sally Ann Lynch, Sarju G. Mehta, Anke Van Dijck, Megan T. Cho, Alison Male, Erik C. Madsen, Katrina Haude, Marvin R. Natowicz, Pradeep Vasudevan, Jacques C. Giltay, Kyle Retterer, Alison Ross, Kristin Lindstrom, Han G. Brunner, Katherine H. Kim, Michael Parker, A. Micheil Innes, Bart Loeys, R. Frank Kooy, Joel Charrow, Kristin G. Monaghan, Eric Haan, Michael C. Kruer, Margot R.F. Reijnders, Andreas Rump, Rolph Pfundt, Lot Snijders Blok, Quinn Stein, Jozef Gecz, Audrey Foster-Barber, Elaine H. Zackai, Karin Oberndorff, Kees E. P. van Roozendaal, Alan Fryer, Ruth Newbury-Ecob, Nataliya Di Donato, Kate Chandler, Alex Henderson, Céline Helsmoortel, Igor Pediaditakis, Bregje W.M. van Bon, Eden Haverfield, Corrado Romano, Sybe Dijkstra, Evan E. Eichler, Connie T.R.M. Stumpel, Hilary Racher, DDD Study, RS: GROW - Developmental Biology, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Klinische Genetica (5), and RS: GROW - R4 - Reproductive and Perinatal Medicine

Subjects
Male, Embryo, Nonmammalian, Gene Dosage, Case Reports, Bioinformatics, medicine.disease_cause, Medical and Health Sciences, BETA-CATENIN, DEAD-box RNA Helicases, 5. Gender equality, 2.1 Biological and endogenous factors, Missense mutation, Exome, Genetics(clinical), HUMAN Y-CHROMOSOME, Aetiology, 10. No inequality, Non-U.S. Gov't, Wnt Signaling Pathway, Zebrafish, Genetics (clinical), X chromosome, Exome sequencing, Genetics & Heredity, Genetics, Mutation, Sex Characteristics, WNT/BETA-CATENIN, Nonmammalian, Research Support, Non-U.S. Gov't, Biological Sciences, Hypotonia, Phenotype, DOMINANT, DIFFERENTIATION, Embryo, Female, medicine.symptom, Sequence Analysis, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Intellectual and Developmental Disabilities (IDD), Molecular Sequence Data, Mutation, Missense, Context (language use), Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], Biology, Research Support, X-inactivation, N.I.H, Research Support, N.I.H., Extramural, X-CHROMOSOME INACTIVATION, Clinical Research, Intellectual Disability, Report, medicine, Journal Article, Animals, Humans, NEURECTODERM, DDD Study, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, ZEBRAFISH, Human Genome, Extramural, DNA, Sequence Analysis, DNA, Brain Disorders, Amino Acid Substitution, RNA, Human medicine, Missense, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], MENTAL-RETARDATION
Abstract

Contains fulltext : 153453.pdf (Publisher’s version ) (Open Access) Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Published
2015

11. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

Antonio Vitobello, Christel Depienne, Kelly Radtke, Bruria Ben-Zeev, Vaidutis Kučinskas, Hirofumi Kashii, Leslie Granger, Florence Demurger, Adi Vaknin-Dembinsky, Androu Waheeb, Takeshi Mizuguchi, Lip H. Moey, Urania Kotzaeridou, Frédérique Béna, Fernando Kok, Timothy Blake Palculict, Yasmin Hamzavi Abedi, Satoko Miyatake, Anne-Sophie Denommé-Pichon, Linda Manwaring, Laura Elena Orec, Laurens Wiel, Han G. Brunner, Sylvie Odent, Eric Vilain, Linh Tran, Simon E. Fisher, Emmanuèlle C. Délot, Vidya Krishnamurthy, Rebecca C. Spillmann, Hilary Coon, Shelagh Joss, Hui B. Chew, Matias Wagner, David A. Dyment, Kirsty McWalter, Michael W. Parker, Adam Jackson, Margje Sinnema, Pengfei Liu, Elke de Boer, Alma Kuechler, Christoffer Nellåker, Christian Gilissen, Yasuo Hachiya, Marcia C. Willing, Shivarajan M. Amudhavalli, Alexander P.A. Stegmann, Ange-Line Bruel, Siddharth Banka, Joery den Hoed, Vardiella Meiner, Rosalyn Jewell, Britton D Zuccarelli, Alexander J. M. Dingemans, Kelly L. Jones, Anja A. Kattentidt-Mouravieva, Matthew Osmond, Orly Elpeleg, Andrea K. Petersen, Nicolas Guex, Dianne F. Newbury, Jill A. Rosenfeld, Alexandre Reymond, Mohamad A. Mikati, Tjitske Kleefstra, Lisenka E.L.M. Vissers, Naomichi Matsumoto, Vincent R. Bonagura, Loreta Cimbalistienė, Benoît Mazel, Hayley S. Mountford, Isabelle Thiffault, Rolph Pfundt, Ruth Newbury-Ecob, Teresa Santiago-Sim, Alinoë Lavillaureix, Eglė Preikšaitienė, Jacqueline Chrast, Toshiyuki Itai, Norine Voisin, Usha Kini, Emmanuelle Ranza, Caitlin Schwager, Brooke Horist, Samantha A. Schrier Vergano, Jennifer Hanebeck, Juliana H. Vedovato-dos-Santos, Mitsuhiro Kato, Theresa Brunet, Lot Snijders Blok, Jayne Y. Hehir-Kwa, Shehla Mohammed, Benjamin Haber, Hagar Mor-Shaked, Laurence Faivre, Dian Donnai, Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Université de Lausanne = University of Lausanne (UNIL), Children's Mercy Hospital [Kansas City], University of Manchester [Manchester], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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 ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Radboud University [Nijmegen], Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, University of Lausanne (UNIL), 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), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Radboud university [Nijmegen], The DDD study, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA Klinische Genetica (5)

Subjects
0301 basic medicine, Male, Models, Molecular, MISSENSE MUTATIONS, CHROMATIN, Transcription, Genetic, Cell, Medizin, Disease, Haploinsufficiency, medicine.disease_cause, 0302 clinical medicine, Missense mutation, de novo variants, Genetics (clinical), INTERLEUKIN-2, seizures, Genetics, 0303 health sciences, Mutation, Chromatin binding, neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], SATB1, Phenotype, medicine.anatomical_structure, intellectual disability, Female, teeth abnormalities, Protein Binding, Neuroinformatics, EXPRESSION, GENES, Mutation, Missense, Biology, BINDING PROTEIN, REGION, 03 medical and health sciences, Protein Domains, Report, medicine, HPO-based analysis, Humans, Genetic Association Studies, Hpo-based Analysis, Satb1, Cell-based Functional Assays, De Novo Variants, Intellectual Disability, Neurodevelopmental Disorders, Seizures, Teeth Abnormalities, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Matrix Attachment Region Binding Proteins, 030104 developmental biology, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery, cell-based functional assays
Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene,SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carryingSATB1variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

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