Author: "Ingrid M. Wentzensen" - Searchworks@Jio Institute Digital Library Search Results

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1. MGA-related syndrome: A proposed novel disorder

Author: Bobbi McGivern, Michelle M. Morrow, Erin Torti, Kirsty McWalter, Ingrid M. Wentzensen, Kristin G. Monaghan, Amanda Gerard, Laurie Robak, David Chitayat, Claire Botsford, Sarah Jurgensmeyer, Peter Leahy, and Paul Kruszka
Subjects: MGA, clinical exome sequencing, candidate gene, gene discovery, congenital anomalies, neurodevelopmental disorder, Genetics, QH426-470
Abstract: Summary: MGA (OMIM: 616061) encodes a dual-specificity transcription factor that regulates the expression of Max-network and T-box family target genes, important in embryogenesis. Previous studies have linked MGA to various phenotypes, including neurodevelopmental disorders, congenital heart disease, and early-onset Parkinson’s disease. Here, we describe the clinical phenotype of individuals with de novo, heterozygous predicted loss-of-function variants in MGA, suggesting a unique disorder involving both neurodevelopmental and congenital anomalies. In addition to developmental delays, certain congenital anomalies were present in all individuals in this cohort including cardiac anomalies, male genital malformations, and craniofacial dysmorphisms. Additional findings seen in multiple individuals in this cohort include hypotonia, abnormal brain imaging, hearing loss, sleep dysfunction, urinary issues, skeletal abnormalities, and feeding difficulties. These findings provide support for MGA as a gene intolerant to protein truncation with a broad phenotypic spectrum.
Published: 2025
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2. LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder

Author: James Chettle, Raymond J. Louie, Olivia Larner, Robert Best, Kevin Chen, Josephine Morris, Zinaida Dedeic, Anna Childers, R. Curtis Rogers, Barbara R. DuPont, Cindy Skinner, Sébastien Küry, Kevin Uguen, Marc Planes, Danielle Monteil, Megan Li, Aviva Eliyahu, Lior Greenbaum, Nofar Mor, Thomas Besnard, Bertrand Isidor, Benjamin Cogné, Alyssa Blesson, Anne Comi, Ingrid M. Wentzensen, Blake Vuocolo, Seema R. Lalani, Roberta Sierra, Lori Berry, Kent Carter, Stephan J. Sanders, and Sarah P. Blagden
Subjects: LARP1, autism, ASD, NDD, neurodevelopmental, metabolism, Genetics, QH426-470
Abstract: Summary: Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.
Published: 2024
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3. Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

Author: Sheng-Jia Lin, Barbara Vona, Tracy Lau, Kevin Huang, Maha S. Zaki, Huda Shujaa Aldeen, Ehsan Ghayoor Karimiani, Clarissa Rocca, Mahmoud M. Noureldeen, Ahmed K. Saad, Cassidy Petree, Tobias Bartolomaeus, Rami Abou Jamra, Giovanni Zifarelli, Aditi Gotkhindikar, Ingrid M. Wentzensen, Mingjuan Liao, Emalyn Elise Cork, Pratishtha Varshney, Narges Hashemi, Mohammad Hasan Mohammadi, Aboulfazl Rad, Juanita Neira, Mehran Beiraghi Toosi, Cordula Knopp, Ingo Kurth, Thomas D. Challman, Rebecca Smith, Asmahan Abdalla, Thomas Haaf, Mohnish Suri, Manali Joshi, Wendy K. Chung, Andres Moreno-De-Luca, Henry Houlden, Reza Maroofian, and Gaurav K. Varshney
Subjects: 2-oxo acid dehydrogenase, OGDHL, Genetic compensation, Disease model, Zebrafish, Neurodevelopmental disorders, Medicine, Genetics, QH426-470
Abstract: Abstract Background Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. Methods Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. Results A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. Conclusions Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as “OGDHL-related disorders”.
Published: 2023
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4. Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Author: Yu-Ri Lee, Kamal Khan, Kim Armfield-Uhas, Sujata Srikanth, Nicola A. Thompson, Mercedes Pardo, Lu Yu, Joy W. Norris, Yunhui Peng, Karen W. Gripp, Kirk A. Aleck, Chumei Li, Ed Spence, Tae-Ik Choi, Soo Jeong Kwon, Hee-Moon Park, Daseuli Yu, Won Do Heo, Marie R. Mooney, Shahid M. Baig, Ingrid M. Wentzensen, Aida Telegrafi, Kirsty McWalter, Trevor Moreland, Chelsea Roadhouse, Keri Ramsey, Michael J. Lyons, Cindy Skinner, Emil Alexov, Nicholas Katsanis, Roger E. Stevenson, Jyoti S. Choudhary, David J. Adams, Cheol-Hee Kim, Erica E. Davis, and Charles E. Schwartz
Subjects: Science
Abstract: Armfield X-linked disability (XLID) disorder has previously been linked to a locus in Xq28. Here, the authors report rare missense variants in FAM50A at Xq28, show that FAM50A interacts with the spliceosome, and that mis-splicing is enriched in knockout zebrafish suggesting it is a spliceosomopathy.
Published: 2020
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5. A recurrent, de novo pathogenic variant in ARPC4 disrupts actin filament formation and causes microcephaly and speech delay

Author: Dianne Laboy Cintron, Alison M. Muir, Abbey Scott, Marie McDonald, Kristin G. Monaghan, Teresa Santiago-Sim, Ingrid M. Wentzensen, Chiara De Luca, Francesco Brancati, David J. Harris, Cecilia Goueli, Rolf Stottmann, Carlos E. Prada, Marta Biderman Waberski, and Heather C. Mefford
Subjects: actin, microcephaly, ARPC4, developmental delay, de novo, genetic, Genetics, QH426-470
Abstract: Summary: We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]). Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex, which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous ARPC4 missense variants as a cause of neurodevelopmental disorders and microcephaly.
Published: 2022
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6. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author: Lot Snijders Blok, Justine Rousseau, Joanna Twist, Sophie Ehresmann, Motoki Takaku, Hanka Venselaar, Lance H. Rodan, Catherine B. Nowak, Jessica Douglas, Kathryn J. Swoboda, Marcie A. Steeves, Inderneel Sahai, Connie T. R. M. Stumpel, Alexander P. A. Stegmann, Patricia Wheeler, Marcia Willing, Elise Fiala, Aaina Kochhar, William T. Gibson, Ana S. A. Cohen, Ruky Agbahovbe, A. Micheil Innes, P. Y. Billie Au, Julia Rankin, Ilse J. Anderson, Steven A. Skinner, Raymond J. Louie, Hannah E. Warren, Alexandra Afenjar, Boris Keren, Caroline Nava, Julien Buratti, Arnaud Isapof, Diana Rodriguez, Raymond Lewandowski, Jennifer Propst, Ton van Essen, Murim Choi, Sangmoon Lee, Jong H. Chae, Susan Price, Rhonda E. Schnur, Ganka Douglas, Ingrid M. Wentzensen, Christiane Zweier, André Reis, Martin G. Bialer, Christine Moore, Marije Koopmans, Eva H. Brilstra, Glen R. Monroe, Koen L. I. van Gassen, Ellen van Binsbergen, Ruth Newbury-Ecob, Lucy Bownass, Ingrid Bader, Johannes A. Mayr, Saskia B. Wortmann, Kathy J. Jakielski, Edythe A. Strand, Katja Kloth, Tatjana Bierhals, The DDD study, John D. Roberts, Robert M. Petrovich, Shinichi Machida, Hitoshi Kurumizaka, Stefan Lelieveld, Rolph Pfundt, Sandra Jansen, Pelagia Deriziotis, Laurence Faivre, Julien Thevenon, Mirna Assoum, Lawrence Shriberg, Tjitske Kleefstra, Han G. Brunner, Paul A. Wade, Simon E. Fisher, and Philippe M. Campeau
Subjects: Science
Abstract: The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.
Published: 2019
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7. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author: Lot Snijders Blok, Justine Rousseau, Joanna Twist, Sophie Ehresmann, Motoki Takaku, Hanka Venselaar, Lance H. Rodan, Catherine B. Nowak, Jessica Douglas, Kathryn J. Swoboda, Marcie A. Steeves, Inderneel Sahai, Connie T. R. M. Stumpel, Alexander P. A. Stegmann, Patricia Wheeler, Marcia Willing, Elise Fiala, Aaina Kochhar, William T. Gibson, Ana S. A. Cohen, Ruky Agbahovbe, A. Micheil Innes, P. Y. Billie Au, Julia Rankin, Ilse J. Anderson, Steven A. Skinner, Raymond J. Louie, Hannah E. Warren, Alexandra Afenjar, Boris Keren, Caroline Nava, Julien Buratti, Arnaud Isapof, Diana Rodriguez, Raymond Lewandowski, Jennifer Propst, Ton van Essen, Murim Choi, Sangmoon Lee, Jong H. Chae, Susan Price, Rhonda E. Schnur, Ganka Douglas, Ingrid M. Wentzensen, Christiane Zweier, André Reis, Martin G. Bialer, Christine Moore, Marije Koopmans, Eva H. Brilstra, Glen R. Monroe, Koen L. I. van Gassen, Ellen van Binsbergen, Ruth Newbury-Ecob, Lucy Bownass, Ingrid Bader, Johannes A. Mayr, Saskia B. Wortmann, Kathy J. Jakielski, Edythe A. Strand, Katja Kloth, Tatjana Bierhals, The DDD study, John D. Roberts, Robert M. Petrovich, Shinichi Machida, Hitoshi Kurumizaka, Stefan Lelieveld, Rolph Pfundt, Sandra Jansen, Pelagia Deriziotis, Laurence Faivre, Julien Thevenon, Mirna Assoum, Lawrence Shriberg, Tjitske Kleefstra, Han G. Brunner, Paul A. Wade, Simon E. Fisher, and Philippe M. Campeau
Subjects: Science
Abstract: Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.
Published: 2018
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8. Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Author: Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, Stephanie M. Robert, Sunday S. Josiah, Emre Kiziltug, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Adam J. Kundishora, Le T. Hao, Hong Li, Roger E. Stevenson, Raymond J. Louie, Wallid Deb, Erin Torti, Virginie Vignard, Kirsty McWalter, F. Lucy Raymond, Farrah Rajabi, Emmanuelle Ranza, Detelina Grozeva, Stephanie A. Coury, Xavier Blanc, Elise Brischoux-Boucher, Boris Keren, Katrin Õunap, Karit Reinson, Pilvi Ilves, Ingrid M. Wentzensen, Eileen E. Barr, Solveig Heide Guihard, Perrine Charles, Eleanor G. Seaby, Kristin G. Monaghan, Marlène Rio, Yolande van Bever, Marjon van Slegtenhorst, Wendy K. Chung, Ashley Wilson, Delphine Quinquis, Flora Bréhéret, Kyle Retterer, Pierre Lindenbaum, Emmanuel Scalais, Lindsay Rhodes, Katrien Stouffs, Elaine M. Pereira, Sara M. Berger, Sarah S. Milla, Ankita B. Jaykumar, Melanie H. Cobb, Shreyas Panchagnula, Phan Q. Duy, Marie Vincent, Sandra Mercier, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Séverine Audebert-Bellanger, Sylvie Odent, Sébastien Schmitt, Pierre Boisseau, Dominique Bonneau, Annick Toutain, Estelle Colin, Laurent Pasquier, Richard Redon, Arjan Bouman, Jill. A. Rosenfeld, Michael J. Friez, Helena Pérez-Peña, Syed Raza Akhtar Rizvi, Shozeb Haider, Stylianos E. Antonarakis, Charles E. Schwartz, Francisco Martínez, Stéphane Bézieau, Kristopher T. Kahle, Bertrand Isidor, Clinical Genetics, Clinical sciences, Medical Genetics, Reproduction and Genetics, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), University of Exeter, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Greenwood Genetic Center, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], 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 ), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Genève = University of Geneva (UNIGE), Yale School of Medicine [New Haven, Connecticut] (YSM), This work was granted by the French network of University Hospitals HUGO ('Hôpitaux Universitaires du Grand Ouest'), the French Ministry of Health, and and the Health Regional Agencies from Poitou-Charentes (represented by Frédérique Allaire), Bretagne, Pays de la Loire, and Centre-Val de Loire (HUGODIMS, 2013, RC14_0107). W.K.C. was supported by grants from Simons Foundation Autism Research Initiative, United
Subjects: MESH: Symporters, Exome sequencing, Male, KCC2, Mutation, Missense, MESH: Catalytic Domain, Neurodevelopmental disease, Protein Serine-Threonine Kinases, X-linked intellectual disability, MESH: Brain, WNK3, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Catalytic Domain, MESH: Mental Retardation, X-Linked, Humans, Phosphorylation, MESH: Hemizygote, Genetics (clinical), Hemizygote, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Phosphorylation, Symporters, Brain, MESH: Loss of Function Mutation, MESH: Protein Serine-Threonine Kinases, MESH: Male, Mental Retardation, X-Linked, Maternal Inheritance, MESH: Maternal Inheritance
Abstract: PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
Published: 2022
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9. Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

Author: Sébastien Küry, Frédéric Ebstein, Alice Mollé, Thomas Besnard, Ming-Kang Lee, Virginie Vignard, Tiphaine Hery, Mathilde Nizon, Grazia M.S. Mancini, Jacques C. Giltay, Benjamin Cogné, Kirsty McWalter, Wallid Deb, Hagar Mor-Shaked, Hong Li, Rhonda E. Schnur, Ingrid M. Wentzensen, Anne-Sophie Denommé-Pichon, Cynthia Fourgeux, Frans W. Verheijen, Eva Faurie, Rachel Schot, Cathy A. Stevens, Daphne J. Smits, Eileen Barr, Ruth Sheffer, Jonathan A. Bernstein, Chandler L. Stimach, Eliana Kovitch, Vandana Shashi, Kelly Schoch, Whitney Smith, Richard H. van Jaarsveld, Anna C.E. Hurst, Kirstin Smith, Evan H. Baugh, Suzanne G. Bohm, Emílie Vyhnálková, Lukáš Ryba, Capucine Delnatte, Juanita Neira, Dominique Bonneau, Annick Toutain, Jill A. Rosenfeld, Séverine Audebert-Bellanger, Brigitte Gilbert-Dussardier, Sylvie Odent, Frédéric Laumonnier, Seth I. Berger, Ann C.M. Smith, Franck Bourdeaut, Marc-Henri Stern, Richard Redon, Elke Krüger, Raphaël Margueron, Stéphane Bézieau, Jeremie Poschmann, Bertrand Isidor, Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Universität Greifswald - University of Greifswald, Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center [Utrecht], GeneDx [Gaithersburg, MD, USA], Hadassah Hebrew University Medical Center [Jerusalem], Emory University School of Medicine, Emory University [Atlanta, GA], Laboratoire de Biologie Neurovasculaire Intégrée [Angers] (CNRS UMR6214 - INSERM U771), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Tennessee System, Stanford University, Duke University Medical Center, University of Alabama at Birmingham [ Birmingham] (UAB), Columbia University [New York], Charles University [Prague] (CU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Baylor College of Medicine (BCM), Baylor University, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, CHU Pontchaillou [Rennes], 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 ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], Children's National Medical Center, National Human Genome Research Institute (NHGRI), Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Greifswald University Hospital, Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672 to V.S. Further support was obtained by funding from the German Research Foundation (SFBTR 167 A4, GRK2719 B4) to E.K, and Clinical Genetics
Subjects: Male, Heterozygote, Proteasome Endopeptidase Complex, tumor, Adolescent, T-Lymphocytes, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Mutation, Missense, UPS, ubiquitin-proteasome system, chromatin remodeling, Histones, SDG 3 - Good Health and Well-being, Loss of Function Mutation, Report, ubiquitin, Genetics, Humans, cancer, Family, BAP1, Child, deubiquitination, Germ-Line Mutation, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, neurodevelopment, BRCA1 Protein, Tumor Suppressor Proteins, Ubiquitination, Infant, Chromatin Assembly and Disassembly, BRCA1, Chromatin, Gene Expression Regulation, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, histone 2A, Female, Host Cell Factor C1, Ubiquitin Thiolesterase
Abstract: International audience; Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.
Published: 2022
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10. Biallelic variants in <scp> TUBGCP6 </scp> result in microcephaly and chorioretinopathy 1: Report of four cases and a literature review

Author: Amanda Thomas‐Wilson, John P. Schacht, David Chitayat, Susan Blaser, Francis Jeshira Reynoso Santos, Kimberly Glaser, Alesky Caffo, Ingrid M. Wentzensen, Lindsay B. Henderson, Futao Zhang, Ying Zhu, Ellen Di Corleto, Fabricio da Silva Costa, Rebecca Vink, Ebba Alkhunaizi, Laura Russell, Michael F. Buckley, Tony Roscioli, Elaine Maria Pereira, and Mythily Ganapathi
Subjects: Genetics, Genetics (clinical)
Published: 2023
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11. SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability

Author: Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus LeBlanc, Emma van Reempts, Frederic Tran Mau-Them, Ingrid M. Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J. Louie, Michael J. Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley McConkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R. Roeder, Tadahiro Mitani, Jennifer E. Posey, Daniel Calame, Hagith Yonath, Jill A. Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R. Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello, Bogaert, Elke, Garde, Aurore, Gautier, Thierry, Rooney, Kathleen, Duffourd, Yanni, Leblanc, Pontu, van Reempts, Emma, Tran Mau-Them, Frederic, Wentzensen, Ingrid M, Au, Kit Sing, Richardson, Kate, Northrup, Hope, Gatinois, Vincent, Geneviève, David, Louie, Raymond J, Lyons, Michael J, Laulund, Lone Walentin, Brasch-Andersen, Charlotte, Maxel Juul, Trine, El It, Fatima, Marle, Nathalie, Callier, Patrick, Relator, Raissa, Haghshenas, Sadegheh, Mcconkey, Haley, Kerkhof, Jennifer, Cesario, Claudia, Novelli, Antonio, Brunetti-Pierri, Nicola, Pinelli, Michele, Pennamen, Perrine, Naudion, Sophie, Legendre, Marine, Courdier, Cécile, Trimouille, Aurelien, Fenzy, Martine Doco, Pais, Lynn, Yeung, Alison, Nugent, Kimberly, Roeder, Elizabeth R, Mitani, Tadahiro, Posey, Jennifer E, Calame, Daniel, Yonath, Hagith, Rosenfeld, Jill A, Musante, Luciana, Faletra, Flavio, Montanari, Francesca, Sartor, Giovanna, Vancini, Alessandra, Seri, Marco, Besmond, Claude, Poirier, Karine, Hubert, Laurence, Hemelsoet, Dimitri, Munnich, Arnold, Lupski, James R, Philippe, Christophe, Thauvin-Robinet, Christel, Faivre, Laurence, Sadikovic, Bekim, Govin, Jérôme, Dermaut, Bart, and Vitobello, Antonio
Subjects: SRSF1, splicing, epigenetic signature, Medicine and Health Sciences, Genetics, Drosophila, neurodevelopmental disorder, Genetics (clinical), haploinsufficiency
Abstract: SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.
Published: 2023

12. The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders

Author: Afshin Saffari, Tracy Lau, Homa Tajsharghi, Ehsan Ghayoor Karimiani, Ariana Kariminejad, Stephanie Efthymiou, Giovanni Zifarelli, Tipu Sultan, Mehran Beiraghi Toosi, Sahar Sedighzadeh, Victoria Mok Siu, Juan Darío Ortigoza-Escobar, Aisha M AlShamsi, Shahnaz Ibrahim, Nouriya Abbas Al-Sannaa, Walla Al-Hertani, Whalen Sandra, Mark Tarnopolsky, Shahryar Alavi, Chumei Li, Debra-Lynn Day-Salvatore, Maria Jesús Martínez-González, Kristin M Levandoski, Emma Bedoukian, Suneeta Madan-Khetarpal, Michaela J Idleburg, Minal Juliet Menezes, Aishwarya Siddharth, Konrad Platzer, Henry Oppermann, Martin Smitka, Felicity Collins, Monkol Lek, Mohmmad Shahrooei, Maryam Ghavideldarestani, Isabella Herman, John Rendu, Julien Faure, Janice Baker, Vikas Bhambhani, Laurel Calderwood, Javad Akhondian, Shima Imannezhad, Hanieh Sadat Mirzadeh, Narges Hashemi, Mohammad Doosti, Mojtaba Safi, Najmeh Ahangari, Paria Najarzadeh Torbati, Soheila Abedini, Vincenzo Salpietro, Elif Yilmaz Gulec, Safieh Eshaghian, Mohammadreza Ghazavi, Michael T Pascher, Marina Vogel, Angela Abicht, Sébastien Moutton, Ange-Line Bruel, Claudine Rieubland, Sabina Gallati, Tim M Strom, Hanns Lochmüller, Mohammad Hasan Mohammadi, Javeria Raza Alvi, Elaine H Zackai, Beth A Keena, Cara M Skraban, Seth I Berger, Erin H Andrew, Elham Rahimian, Michelle M Morrow, Ingrid M Wentzensen, Francisca Millan, Lindsay B Henderson, Hormos Salimi Dafsari, Heinz Jungbluth, Natalia Gomez-Ospina, Anne McRae, Merlene Peter, Danai Veltra, Nikolaos M Marinakis, Christalena Sofocleous, Farah Ashrafzadeh, Davut Pehlivan, Johannes R Lemke, Judith Melki, Audrey Benezit, Peter Bauer, Denisa Weis, James R Lupski, Jan Senderek, John Christodoulou, Wendy K Chung, Rose Goodchild, Amaka C Offiah, Andres Moreno-De-Luca, Mohnish Suri, Darius Ebrahimi-Fakhari, Henry Houlden, and Reza Maroofian
Subjects: NDD, biallelic variation, AMC5, 610 Medicine & health, Neurology (clinical), Torsin-1A, 610 Medizin und Gesundheit, arthrogryposis multiplex congenita 5, Medical Genetics, Medicinsk genetik
Abstract: In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival. CC BY 4.0Correspondence to: Reza MaroofianDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UKE-mail: R.Maroofian@ucl.ac.ukA.S. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SA 4171/1-1. H.H. is funded by The MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). S.E. is supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1’. This work was supported in part by the US National Institutes of Health R35 NS105078 and MDA#512848 to J.R.L., a jointly funded National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542) and NHGRI Genomics Research to Elucidate Genetics of Rare (BCM-GREGoR U01 HG011758). D.P. is supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation (ABF) and Muscle Study Group (MSG). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children’s Hospital Foundation. H.T. has been supported by the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement no. 608473. H.S.D. is supported by the Cologne Clinician Scientist Program/Faculty of Medicine/University of Cologne and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Project No. 413543196). H.J. has been supported by a grant from the European Union (H2020- MSCA-ITN-2017). A.M.D. is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (grant 1R01HD104938-01A1). H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). This research was funded in part by the Wellcome Trust (WT093205MA, WT104033AIA and the Synaptopathies Strategic Award, 165908) as well as the Medical Research Council (MRC) (MR/S01165X/1, MR/ S005021/1, G0601943). Additonally, we are grateful for funding from The MSA Trust, The National Institute for Health Research University College London Hospitals Biomedical Research Centre, The Michael J Fox Foundation (MJFF), BBSRC, The Fidelity Trust, Rosetrees Trust, Ataxia UK, Brain Research UK, Sparks GOSH Charity, Alzheimer’s Research UK (ARUK) and CureDRPLA.
Published: 2023
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13. UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly

Author: Rory J. Olson, Jane Juusola, Mark Flage, Carlos E. Prada, Srikar Kuppa, Gustavo Adolfo Contreras-García, Camilo A. Peñaloza-Mantilla, Maria J. Guillen Sacoto, Gail E. Graham, Lindsay Rhodes, James Liu, Pavel N. Pichurin, Michael Marble, Regina M. Zambrano, Wendy K. Chung, Parul Jayakar, Matthew J. Schultz, Mary Ella M Pierpont, Karina A. Campo-Neira, Matthew Osmond, Ingrid M. Wentzensen, Sairah Yousaf, Robert B. Hufnagel, Rhonda E. Schnur, Nara Sobreira, Maria I. Scarano, and Karina Navarro
Subjects: 0301 basic medicine, Microcephaly, Ectrodactyly, Limb Deformities, Congenital, Ubiquitin-Activating Enzymes, 030105 genetics & heredity, Microphthalmia, Article, Aplasia cutis congenita, 03 medical and health sciences, Ectodermal Dysplasia, medicine, Animals, Humans, Missense mutation, Abnormalities, Multiple, Zebrafish, Genetics (clinical), Exome sequencing, Loss function, Genetics, biology, medicine.disease, biology.organism_classification, 030104 developmental biology, medicine.symptom
Abstract: Purpose: The human chromosome 19q13.11 deletion syndrome is associated with a variable phenotype that includes aplasia cutis congenita (ACC) and ectrodactyly as specific features. UBA2 (ubiquitin-like modifier-activating enzyme 2) lies adjacent to the minimal deletion overlap region. We aim to define the UBA2-related phenotypic spectrum in humans and zebrafish due to sequence variants and to establish the mechanism of disease. Methods: Exome Sequencing was used to detect UBA2 sequence variants in 16 subjects in 7 unrelated families. uba2 loss-of-function was modeled in zebrafish. Effects of human missense variants were assessed in zebrafish rescue experiments. Results: 7 human UBA2 loss-of-function and missense sequence variants were detected. UBA2-phenotypes included ACC, ectrodactyly, neurodevelopmental abnormalities, ectodermal, skeletal, craniofacial, cardiac, renal, and genital anomalies. uba2 was expressed in zebrafish eye, brain, and pectoral fins; uba2-null fish showed deficient growth, microcephaly, microphthalmia, mandibular hypoplasia, and abnormal fins. uba2-mRNAs with human missense variants failed to rescue nullizygous zebrafish phenotypes. Conclusion: UBA2 variants cause a recognizable syndrome with a wide phenotypic spectrum. Our data suggest that loss of UBA2 function underlies the human UBA2 monogenic disorder and highlights the importance of SUMOylation in the development of affected tissues.
Published: 2021
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14. Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Author: Tugce B. Balci, Paul R. Mark, Sedlácek Z, Krista Sondergaard Schatz, Tadashi Kaname, Christiane Zweier, Hidenori Ohnishi, Ingrid M. Wentzensen, Solveig Heide, Weimin Bi, A. Baxova, Antje Wiesener, Nancy J. Cox, Devon Haynes, David Rodriguez-Buritica, Sarka Bendova, Nobuhiko Okamoto, Tomoko Uehara, Oana Caluseriu, Koichi Kawakami, Victoria Mok Siu, Alfredo Brusco, Boris Keren, Jennifer M. Lemons, David J. Amor, Patrick Rump, Marie T. McDonald, George E. Hoganson, Miroslava Hancarova, Gina M. Morley, Maria A. Magriña, Sarah Montgomery, Lei Wang, Seema R. Lalani, Kazuo Kubota, Mohammed Al-raqad, Patricia G Wheeler, Haley Streff, Fuad Chowdhury, Elisa Biamino, Meral Gunay-Aygun, Tawfiq Froukh, Kenjiro Kosaki, and Jagdeep S. Walia
Subjects: 0301 basic medicine, Haploinsufficiency/genetics, Pathology, medicine.medical_specialty, Mutation, Missense, Haploinsufficiency, 030105 genetics & heredity, Microphthalmia, Frameshift mutation, Intellectual Disability, PRR12, neurodevelopmental disorder, Mice, 03 medical and health sciences, Neurodevelopmental disorder, medicine, Animals, Humans, Missense mutation, Genetics (clinical), Anophthalmia, business.industry, medicine.disease, Intellectual Disability/genetics, Hypotonia, Phenotype, 030104 developmental biology, Mutation, Muscle Hypotonia, Missense, medicine.symptom, business, Kidney disease
Abstract: Purpose: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. Methods: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. Results: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. Conclusion: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities. Graphic Abstract: [Figure not available: see fulltext.]
Published: 2021
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15. <scp>TSPEAR</scp>variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study

Author: Tristan Rey, Abigail Williams, Carla Nishimura, Kirsty McWalter, Alex Cummings, Agnès Bloch-Zupan, Francesca Clementina Radio, Bruno Dallapiccola, Dusica Babovic-Vuksanovic, Maria Lisa Dentici, Emanuele Agolini, Filippo Vairo, J. Austin Hamm, Jennifer A. Sullivan, Kelly Schoch, Brendan C. Lanpher, Chelsea Roadhouse, Ingrid M. Wentzensen, Richard J.H. Smith, Alejandro Ferrer, Arun Ankala, Chumei Li, Sara Loddo, Bradley Bowles, Dario Cocciadiferro, Bénédicte Gérard, Nicholas Stong, Eric W. Klee, Silvia Genovese, Vandana Shashi, and Bruno Leheup
Subjects: Male, Ectodermal dysplasia, Hearing loss, TSPEAR, Cohort Studies, otorhinolaryngologic diseases, Genetics, medicine, Humans, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Exome sequencing, hearing loss, Anodontia, Genetic testing, medicine.diagnostic_test, biology, business.industry, Genetic Variation, Proteins, Original Articles, medicine.disease, Phenotype, ectodermal dysplasia, Pedigree, Radiography, Amino Acid Substitution, Genetic Loci, Mutation, biology.protein, Original Article, Female, medicine.symptom, business, GJB6, autosomal recessive deafness, tooth agenesis, Cohort study
Abstract: Biallelic loss‐of‐function variants in the thrombospondin‐type laminin G domain and epilepsy‐associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype–phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel‐based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing‐loss‐associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.
Published: 2021
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16. Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3—a subgroup of K+ channelopathies

Author: Karen W. Gripp, Ingrid M. Wentzensen, Julie D. Kaplan, Lindsay B. Henderson, Germaine Pierre, Maggie Williams, Anne McRae, Kerstin Kutsche, Jean-Marc Good, Julia Baptista, Marleen Simon, Anirban Majumdar, Mary Beth Dinulos, Andrea Superti-Furga, Ellen van Binsbergen, Lisette Leeuwen, Ingrid Scurr, Sarah F. Smithson, and Heather M. McLaughlin
Subjects: Adult, Male, 0301 basic medicine, Hypertrichosis, Potassium Channels, Adolescent, Small-Conductance Calcium-Activated Potassium Channels, Nails, Malformed, Biology, Article, Craniofacial Abnormalities, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual Disability, Genetics research, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, Child, Gene, Genetics (clinical), Fibromatosis, Gingival, Abnormalities, Multiple/genetics, Abnormalities, Multiple/pathology, Channelopathies/genetics, Channelopathies/pathology, Craniofacial Abnormalities/genetics, Craniofacial Abnormalities/pathology, Ether-A-Go-Go Potassium Channels/genetics, Female, Fibromatosis, Gingival/genetics, Fibromatosis, Gingival/pathology, Gain of Function Mutation, Hallux/abnormalities, Hallux/pathology, Hand Deformities, Congenital/genetics, Hand Deformities, Congenital/pathology, Intellectual Disability/genetics, Intellectual Disability/pathology, Nails, Malformed/genetics, Nails, Malformed/pathology, Phenotype, Potassium Channels/genetics, Small-Conductance Calcium-Activated Potassium Channels/genetics, Thumb/abnormalities, Thumb/pathology, Coarse facial features, medicine.disease, Ether-A-Go-Go Potassium Channels, Paediatric neurological disorders, 030104 developmental biology, Thumb, KCNK4, Hallux, Channelopathies, Hand Deformities, Congenital, 030217 neurology & neurosurgery
Abstract: Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann–Laband and Temple–Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
Published: 2021
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17. Variants in GNAI1 Cause a Syndrome Associated with Variable Features including Developmental Delay, Seizures and Hypotonia

Author: Lauren Brady, Bryan E. Hainline, Konrad Platzer, Muhammad Zafar, Corinna Powell, Darcy J. Huismann, Heather C Mefford, Afnan Alhakeem, Daniel G. MacArthur, Alison M. Muir, Trevor L Hoffman, Mark A. Tarnopolsky, François Lecoquierre, Lindsay Rhodes, Tilman Polster, Susanne Axer-Schaefer, Alice Goldenberg, Katherine Sapp, Caoimhe S. McKenna, Jasper J. van der Smagt, Tara Montgomery, Eleina M. England, Brianna K. Murray, Myriam Srour, Lia Zitano, William B. Dobyns, Grace Noh, Angela F. Brady, Lindsey Sawyer, Ingrid M. Wentzensen, Holly Dubbs, Jane Juusola, Richard Caswell, Richard H. van Jaarsveld, Danielle DeMarzo, Samantha A. Schrier Vergano, Caleb Bupp, Grace E. VanNoy, Jose E. Martinez, Melanie O’Leary, Iris M de Lange, Shane McKee, Golder N. Wilson, Rhonda E. Schnur, Meira Meltzer, Vinod Varghese, Kristin G. Monaghan, Carole Brewer, Carolyn Tysoe, Jennifer F. Gardner, Ethan M. Goldberg, Shelagh Joss, Andrea Accogli, Chiara Klöckner, Andrea L. Gropman, and Pradeep C. Vasudevan
Subjects: 0301 basic medicine, Developmental Disabilities, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Epilepsy, Neurodevelopmental disorder, Seizures, Intellectual Disability, Intellectual disability, Exome Sequencing, medicine, Humans, Global developmental delay, Child, Genetics (clinical), Exome sequencing, Genetics, Genetic heterogeneity, medicine.disease, Hypotonia, 030104 developmental biology, Neurodevelopmental Disorders, Autism, Muscle Hypotonia, medicine.symptom
Abstract: Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and one was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
Published: 2021

18. Expanding the Phenotype of TUBB2A-Related Tubulinopathy: Three Cases of a Novel, Heterozygous TUBB2A Pathogenic Variant p.Gly98Arg

Author: Maria J. Guillen Sacoto, Lindsey Schmidt, Juvianee I Estrada-Veras, Denise L. Perry, Alka Malhotra, Andres Moreno-De-Luca, Megan Bell, Karen E. Wain, Catherine Hajek, Ingrid M. Wentzensen, and Amanda Clause
Subjects: Genetics, 0303 health sciences, 030305 genetics & heredity, Biology, Cortical dysplasia, medicine.disease, Hypotonia, 03 medical and health sciences, Autism spectrum disorder, medicine, Autism, Missense mutation, Global developmental delay, medicine.symptom, Exome, Genetics (clinical), Exome sequencing, 030304 developmental biology
Abstract: Tubulinopathies are a group of conditions caused by variants in 6 tubulin genes that present with a spectrum of brain malformations. One of these conditions is TUBB2A-related tubulinopathy. Currently, there are 9 reported individuals with pathogenic variants within the TUBB2A gene, with common manifestations including, but not limited to, global developmental delay, seizures, cortical dysplasia, and dysmorphic corpus callosum. We report 3 patients identified by exome and genome sequencing to have a novel, pathogenic, missense variant in TUBB2A (p.Gly98Arg). They presented similarly with intellectual disability, hypotonia, and global developmental delay and varied with respect to the type of cortical brain malformation, seizure history, diagnosis of autism spectrum disorder, and other features. This case series expands the natural history of TUBB2A-related tubulinopathy while describing the presentation of a novel, pathogenic, missense variant in 3 patients.
Published: 2020
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19. Genotype-phenotype correlation at codon 1740 ofSETD2

Author: Bernt Popp, Shelby Romoser, Lara Menzies, Stacey A. Bélanger, Alireza Radmanesh, Kimberly A. Aldinger, Jennifer Keller-Ramey, Janice Baker, Jane A. Hurst, William B. Dobyns, Schahram Akbarian, Sébastien Jacquemont, Jan Maarten Cobben, Larissa Kerecuk, Kelly Radtke, Joseph T. Shieh, Khadije Jizi, Ian A. Glass, Patrick Watts, Nicola Foulds, Jerica Lenberg, Sumit Punj, George E. Hoganson, Nancy J. Mendelsohn, Rachel Rabin, Ina Sorge, Katarzyna A. Ellsworth, Katharina Löhner, Manuela Siekmeyer, Jennifer Burton, Leah Dowsett, John A. Bernat, Hannah Bombei, John Pappas, Henny H. Lemmink, Francis H. Sansbury, Ingrid M. Wentzensen, Kirsty McWalter, Deborah Osio, Pamela Trapane, Hermine E. Veenstra-Knol, General Paediatrics, Paediatric Genetics, and ANS - Complex Trait Genetics
Subjects: Male, Microcephaly, Mutation, Missense, Biology, Nervous System Malformations, Epigenesis, Genetic, Histone H3, Loss of Function Mutation, Tubulin, SETD2, Intellectual Disability, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, histone modification, Epigenetics, AUTISM, Child, Codon, Genetic Association Studies, Genetics (clinical), Loss function, HYPB/SETD2, MARK, IDENTIFICATION, MUTATIONS, METHYLATION, Infant, Histone-Lysine N-Methyltransferase, Methylation, neurodevelopmental, medicine.disease, Histone, genotype phenotype, Neurodevelopmental Disorders, Child, Preschool, biology.protein, Female, clinical genetics
Abstract: The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.
Published: 2020
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20. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Author: Cheryl Cytrynbaum, Francesca Mattioli, Maria J. Guillen Sacoto, Federico Santoni, Rosanna Weksberg, Amina Nasar, Annemarie Fock, Henry Houlden, Shaikh Riazuddin, Tobias B. Haack, Roisin Sullivan, Mona Grimmel, Helen Griffin, Stylianos E. Antonarakis, Nuzhat Rana, Andreea Manole, Marisa I. Mendes, Ayca Dilruba Aslanger, Justyna Iwaszkiewicz, Julia Mohr, Rolph Pfundt, Muhammed Ilyas, Tina Duelund Hjortshøj, Kshitij Mankad, Muhammad Ansar, Katherine M. Christensen, Sonal Desai, Aida Telegrafi, Faisal Zafar, Helena Gásdal Karstensen, Dagan Jenkins, Yue Si, John F. Mantovani, Alice Goldenberg, Sylvain Debard, Muhammad T. Sarwar, Jagdeep S. Walia, Stephanie Efthymiou, Rita Horvath, Vincenzo Salpietro, Reza Maroofian, Jawad Ahmed, Joost Raaphorst, Lindsay B. Henderson, Benyekhlef Kara, Lauren Badalato, Adnan Y. Manzur, Desirée E.C. Smith, Ruben Portier, Marwan Shinawi, Marisa V. Andrews, Gajja S. Salomons, John B. Vincent, Amélie Piton, Felix Distelmaier, Emmanuelle Ranza, Jean-Louis Mandel, Sohail A. Paracha, Marybeth Hummel, Jürg Bähler, Dustin Baldridge, Muhammad A. Usmani, Lu Wang, Maria Rodriguez Lopez, Frédéric Fischer, Annette Seibt, Servi J. C. Stevens, Matthew J. Jennings, Majdi Kara, Amelia Kirby, Hubert Dominique Becker, Kristin W. Barañano, Christopher S. Francklyn, Saima Riazuddin, Rasim Ozgur Rosti, Emer O'Connor, Yalda Jamshidi, Barbara Oehl-Jaschkowitz, Ricardo Harripaul, Anne Marie Jelsig, Anna Sarkozy, Indran Davagnanam, Zubair M. Ahmed, David A. Koolen, Joseph G. Gleeson, Heinz Gabriel, Alkyoni Athanasiou-Fragkouli, Muhammad Ayub, Alejandro Horga, Conny van Ravenwaaij, Bruno Senger, Ingrid M. Wentzensen, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurology, Laboratory Genetic Metabolic Diseases, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ASLANGER, Ayça Dilruba, Université de Strasbourg (UNISTRA), MUMC+: DA KG Lab Centraal Lab (9), RS: FHML non-thematic output, Laboratory Medicine, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Gastroenterology Endocrinology Metabolism, and Amsterdam Reproduction & Development (AR&D)
Subjects: Male, 0301 basic medicine, Microcephaly, Developmental delay, [SDV]Life Sciences [q-bio], Aspartate-tRNA Ligase, TRANSFER-RNA SYNTHETASE, RNA, Transfer, Amino Acyl, 0302 clinical medicine, RNA, Transfer, Loss of Function Mutation, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), next generation sequencing, chemistry.chemical_classification, Genetics, neurodevelopment, Stem Cells, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Neural stem cell, Pedigree, Amino acid, developmental delay, Gain of Function Mutation, Transfer RNA, Female, Amino Acyl, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], EXPRESSION, Ataxia, Biology, Article, Cell Line, Amino Acyl-tRNA Synthetases, 03 medical and health sciences, aminoacyl-tRNA synthetase, epilepsy, neuropathy, Alleles, Genetic Predisposition to Disease, Humans, Neurodevelopmental Disorders, 2 SIBLINGS, medicine, Allele, Epilepsy, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MUTATIONS, medicine.disease, Transfer, 030104 developmental biology, Enzyme, chemistry, Aminoacyl-tRNA synthetase, RNA, 030217 neurology & neurosurgery, Function (biology)
Abstract: Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
Published: 2020
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21. Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Author: Charles E. Schwartz, Emil Alexov, Jyoti S. Choudhary, Sujata Srikanth, Joy Norris, Keri Ramsey, Lu Yu, David J. Adams, Yu-Ri Lee, Karen W. Gripp, Ed Spence, Cheol-Hee Kim, Aida Telegrafi, Roger E. Stevenson, Chelsea Roadhouse, Trevor Moreland, Tae Ik Choi, Soo Jeong Kwon, Hee Moon Park, Erica E. Davis, Ingrid M. Wentzensen, Won Do Heo, Kim Armfield-Uhas, Cindy Skinner, Nicholas Katsanis, Yunhui Peng, Kamal Khan, Mercedes Pardo, Kirsty McWalter, Shahid Mahmood Baig, Marie R. Mooney, Nicola A. Thompson, Michael J. Lyons, Chumei Li, Daseuli Yu, and Kirk Aleck
Subjects: 0301 basic medicine, Male, Molecular biology, General Physics and Astronomy, 030105 genetics & heredity, medicine.disease_cause, Transcriptome, Mice, RNA, Small Nuclear, Missense mutation, lcsh:Science, Child, Zebrafish, Genetics, Mutation, Multidisciplinary, Gene Expression Regulation, Developmental, RNA-Binding Proteins, Syndrome, Phenotype, Pedigree, DNA-Binding Proteins, Protein Transport, Child, Preschool, Female, Adult, Spliceosome, congenital, hereditary, and neonatal diseases and abnormalities, RNA Splicing, Science, Mutation, Missense, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Intellectual Disability, Developmental biology, medicine, Animals, Humans, Family, RNA, Messenger, Cell Nucleus, Alternative splicing, General Chemistry, Zebrafish Proteins, biology.organism_classification, Xq28, nervous system diseases, 030104 developmental biology, Mental Retardation, X-Linked, NIH 3T3 Cells, Spliceosomes, lcsh:Q, Neuroscience
Abstract: Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID). We report rare FAM50A missense variants in the original Armfield XLID syndrome family localized in Xq28 and four additional unrelated males with overlapping features. Our fam50a knockout (KO) zebrafish model exhibits abnormal neurogenesis and craniofacial patterning, and in vivo complementation assays indicate that the patient-derived variants are hypomorphic. RNA sequencing analysis from fam50a KO zebrafish show dysregulation of the transcriptome, with augmented spliceosome mRNAs and depletion of transcripts involved in neurodevelopment. Zebrafish RNA-seq datasets show a preponderance of 3′ alternative splicing events in fam50a KO, suggesting a role in the spliceosome C complex. These data are supported with transcriptomic signatures from cell lines derived from affected individuals and FAM50A protein-protein interaction data. In sum, Armfield XLID syndrome is a spliceosomopathy associated with aberrant mRNA processing during development., Armfield X-linked disability (XLID) disorder has previously been linked to a locus in Xq28. Here, the authors report rare missense variants in FAM50A at Xq28, show that FAM50A interacts with the spliceosome, and that mis-splicing is enriched in knockout zebrafish suggesting it is a spliceosomopathy.
Published: 2020

22. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Author: Sarah E.M. Stephenson, Gregory Costain, Laura E.R. Blok, Michael A. Silk, Thanh Binh Nguyen, Xiaomin Dong, Dana E. Alhuzaimi, James J. Dowling, Susan Walker, Kimberly Amburgey, Robin Z. Hayeems, Lance H. Rodan, Marc A. Schwartz, Jonathan Picker, Sally A. Lynch, Aditi Gupta, Kristen J. Rasmussen, Lisa A. Schimmenti, Eric W. Klee, Zhiyv Niu, Katherine E. Agre, Ilana Chilton, Wendy K. Chung, Anya Revah-Politi, P.Y. Billie Au, Christopher Griffith, Melissa Racobaldo, Annick Raas-Rothschild, Bruria Ben Zeev, Ortal Barel, Sebastien Moutton, Fanny Morice-Picard, Virginie Carmignac, Jenny Cornaton, Nathalie Marle, Orrin Devinsky, Chandler Stimach, Stephanie Burns Wechsler, Bryan E. Hainline, Katie Sapp, Marjolaine Willems, Ange-line Bruel, Kerith-Rae Dias, Carey-Anne Evans, Tony Roscioli, Rani Sachdev, Suzanna E.L. Temple, Ying Zhu, Joshua J. Baker, Ingrid E. Scheffer, Fiona J. Gardiner, Amy L. Schneider, Alison M. Muir, Heather C. Mefford, Amy Crunk, Elizabeth M. Heise, Francisca Millan, Kristin G. Monaghan, Richard Person, Lindsay Rhodes, Sarah Richards, Ingrid M. Wentzensen, Benjamin Cogné, Bertrand Isidor, Mathilde Nizon, Marie Vincent, Thomas Besnard, Amelie Piton, Carlo Marcelis, Kohji Kato, Norihisa Koyama, Tomoo Ogi, Elaine Suk-Ying Goh, Christopher Richmond, David J. Amor, Jessica O. Boyce, Angela T. Morgan, Michael S. Hildebrand, Antony Kaspi, Melanie Bahlo, Rún Friðriksdóttir, Hildigunnur Katrínardóttir, Patrick Sulem, Kári Stefánsson, Hans Tómas Björnsson, Simone Mandelstam, Manuela Morleo, Milena Mariani, Marcello Scala, Andrea Accogli, Annalaura Torella, Valeria Capra, Mathew Wallis, Sandra Jansen, Quinten Waisfisz, Hugoline de Haan, Simon Sadedin, Sze Chern Lim, Susan M. White, David B. Ascher, Annette Schenck, Paul J. Lockhart, John Christodoulou, Tiong Yang Tan, Stephenson, S. E. M., Costain, G., Blok, L. E. R., Silk, M. A., Nguyen, T. B., Dong, X., Alhuzaimi, D. E., Dowling, J. J., Walker, S., Amburgey, K., Hayeems, R. Z., Rodan, L. H., Schwartz, M. A., Picker, J., Lynch, S. A., Gupta, A., Rasmussen, K. J., Schimmenti, L. A., Klee, E. W., Niu, Z., Agre, K. E., Chilton, I., Chung, W. K., Revah-Politi, A., Au, P. Y. B., Griffith, C., Racobaldo, M., Raas-Rothschild, A., Ben Zeev, B., Barel, O., Moutton, S., Morice-Picard, F., Carmignac, V., Cornaton, J., Marle, N., Devinsky, O., Stimach, C., Wechsler, S. B., Hainline, B. E., Sapp, K., Willems, M., Bruel, A. -L., Dias, K. -R., Evans, C. -A., Roscioli, T., Sachdev, R., Temple, S. E. L., Zhu, Y., Baker, J. J., Scheffer, I. E., Gardiner, F. J., Schneider, A. L., Muir, A. M., Mefford, H. C., Crunk, A., Heise, E. M., Millan, F., Monaghan, K. G., Person, R., Rhodes, L., Richards, S., Wentzensen, I. M., Cogne, B., Isidor, B., Nizon, M., Vincent, M., Besnard, T., Piton, A., Marcelis, C., Kato, K., Koyama, N., Ogi, T., Goh, E. S. -Y., Richmond, C., Amor, D. J., Boyce, J. O., Morgan, A. T., Hildebrand, M. S., Kaspi, A., Bahlo, M., Fridriksdottir, R., Katrinardottir, H., Sulem, P., Stefansson, K., Bjornsson, H. T., Mandelstam, S., Morleo, M., Mariani, M., Scala, M., Accogli, A., Torella, A., Capra, V., Wallis, M., Jansen, S., Weisfisz, Q., de Haan, H., Sadedin, S., Lim, S. C., White, S. M., Ascher, D. B., Schenck, A., Lockhart, P. J., Christodoulou, J., Tan, T. Y., and Human genetics
Subjects: F-box protein, Ubiquitin-Protein Ligase, Proteasome Endopeptidase Complex, F-Box-WD Repeat-Containing Protein 7, Ubiquitin-Protein Ligases, Neurodevelopment, global developmental delay, macrocephaly, Germ Cell, Article, All institutes and research themes of the Radboud University Medical Center, FBXW7, Neurodevelopmental Disorder, Genetics, Humans, hypotonia, Germ-Line Mutation, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], brain malformation, Ubiquitination, gastrointestinal issue, Germ Cells, intellectual disability, Neurodevelopmental Disorders, epilepsy, Human
Abstract: Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.
Published: 2022
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23. Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling

Author: Alexander M. Holtz, Rachel VanCoillie, Elizabeth A. Vansickle, Deanna Alexis Carere, Kara Withrow, Erin Torti, Jane Juusola, Francisca Millan, Richard Person, Maria J. Guillen Sacoto, Yue Si, Ingrid M. Wentzensen, Jada Pugh, Georgia Vasileiou, Melissa Rieger, André Reis, Emanuela Argilli, Elliott H. Sherr, Kimberly A. Aldinger, William B. Dobyns, Theresa Brunet, Julia Hoefele, Matias Wagner, Benjamin Haber, Urania Kotzaeridou, Boris Keren, Delphine Heron, Cyril Mignot, Solveig Heide, Thomas Courtin, Julien Buratti, Serini Murugasen, Kirsten A. Donald, Emily O’Heir, Shade Moody, Katherine H. Kim, Barbara K. Burton, Grace Yoon, Miguel del Campo, Diane Masser-Frye, Mariya Kozenko, Christina Parkinson, Susan L. Sell, Patricia L. Gordon, Jeremy W. Prokop, Amel Karaa, Caleb Bupp, and Benjamin A. Raby
Subjects: Nonmuscle Myosin Type IIB, Myosin Heavy Chains, Neurodevelopmental Disorders, Humans, Hedgehog Proteins, Cilia, Genetics (clinical), Actins
Abstract: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis.We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length.These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.
Published: 2021

24. A recurrent, de novo pathogenic variant in ARPC4 disrupts actin filament formation and causes microcephaly and speech delay

Author: David J. Harris, Teresa Santiago Sim, Heather C Mefford, Chiara De Luca, Cecilia Goueli, Alison M. Muir, Kristin G. Monaghan, Carlos E. Prada, Francesco Brancati, Marie T. McDonald, Dianne Laboy Citron, Rolf Stottman, Marta Biderman Waberski, Abbey A. Scott, and Ingrid M. Wentzensen
Subjects: Genetics, Microcephaly, de novo, Protein subunit, QH426-470, Biology, medicine.disease, ARPC4, Protein filament, developmental delay, Neurodevelopmental disorder, Report, Speech delay, medicine, Molecular Medicine, Missense mutation, microcephaly, medicine.symptom, genetic, actin, Gene, Genetics (clinical), Actin
Abstract: Summary We report seven affected individuals from six families with a recurrent, de novo variant in the ARPC4 gene (c.472C>T [p.Arg158Cys (GenBank: NM_005718.4)]). Core features in affected individuals include microcephaly, mild motor delays, and significant speech impairment. ARPC4 is a core subunit of the actin-related protein (ARP2/3) complex, which catalyzes the formation of F-actin networks. We show that the recurrent ARPC4 missense change is associated with a decreased amount of F-actin in cells from two affected individuals. Taken together, our results implicate heterozygous ARPC4 missense variants as a cause of neurodevelopmental disorders and microcephaly., We report a neurodevelopmental disorder with microcephaly in seven affected individuals with the same de novo variant in the ARPC4 gene. The recurrent variant in ARPC4, a subunit of the complex that catalyzes F-actin network formation, is associated with decreased F-actin in cells from affected individuals.
Published: 2021

25. BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations

Author: Øyvind L. Busk, Kimberley Bradbury, Arjan Bouman, Philippe M. Campeau, Lynne M. Bird, Cornelia Kraus, Colleen Carlston, Rong Mao, Juliette Piard, Laurence Faivre, Amanda Openshaw, Catherine Ward Melver, Mohnish Suri, Christiane Zweier, François Guillemot, Rolph Pfundt, Janice C. Palumbos, Parthiv Haldipur, Jane A. Hurst, Kimberly McDonald, Margaux Serey-Gaut, Luitgard Graul-Neumann, Karen J. Low, Jenny Carmichael, Patrick Ferrerira, Birgit Elisabeth Kristiansen, Ange-Line Bruel, Constance Motter, Andrea Accogli, Darrah N. Haffner, Suhair Hanna, Ruta Marcinkute, Angela Peron, Marcella Zollino, Sofia Maia, James Lespinasse, Claire E. Turner, Sally Ann Lynch, Richard E. Person, Valeria Capra, Kimberly A. Aldinger, Constance Smith-Hicks, Gyri Aasland Gradek, Ingrid M. Wentzensen, Megha Desai, Manuela Morleo, Aditi Shah Parikh, Marcello Scala, Cristina Dias, Gunnar Houge, Telethon Undiagnosed Disease Program, Anne Slavotinek, Roberta Battini, Mary J. Green, Anna Chassevent, Tara Montgomery, David Viskochil, Tatiana Tvrdik, Dawn L. Earl, Karin Weiss, Felice D'Arco, William B. Dobyns, Ping Yee Billie Au, Daniah Beleford, Erica F. Andersen, Bert B.A. de Vries, Jill Clayton-Smith, Christophe Philippe, and Michael J. Bamshad
Subjects: business.industry, Postnatal microcephaly, Microdeletion syndrome, medicine.disease, Bioinformatics, Hypotonia, Developmental disorder, Autism spectrum disorder, Intellectual disability, Fetal hemoglobin, medicine, Missense mutation, medicine.symptom, business
Abstract: PurposeHeterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.MethodsWe performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.ResultsMolecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity.ConclusionsWe expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.
Published: 2021
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26. 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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27. Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities

Author: Jennifer A. Lee, Carlos Ferreira, Kym M. Boycott, Lina Basel-Salmon, Yue Si, Richard E. Person, Michael J. Lyons, Melissa T. Carter, Dmitriy Niyazov, Claudia Gonzaga-Jauregui, Renee Bend, Erin Torti, Lior Cohen, Samantha K Rojas, Ingrid M. Wentzensen, and Mohamad A. Mikati
Subjects: Male, Microcephaly, Adolescent, Biology, medicine.disease_cause, Compound heterozygosity, Article, 03 medical and health sciences, Atrophy, Genetics, medicine, Humans, DNA sequencing, Allele, Child, 10. No inequality, Genetics (clinical), Loss function, 0303 health sciences, Mutation, Neurodevelopmental disorders, Medical genetics, 030305 genetics & heredity, Brain, Infant, Protein Tyrosine Phosphatases, Non-Receptor, medicine.disease, Phenotype, Child, Preschool, Female, Ventriculomegaly
Abstract: PTPN23 is a His-domain protein-tyrosine phosphatase implicated in ciliogenesis, the endosomal sorting complex required for transport (ESCRT) pathway, and RNA splicing. Until recently, no defined human phenotype had been associated with alterations in this gene. We identified and report a cohort of seven patients with either homozygous or compound heterozygous rare deleterious variants in PTPN23. Combined with four patients previously reported, a total of 11 patients with this disorder have now been identified. We expand the phenotypic and variation spectrum associated with defects in this gene. Patients have strong phenotypic overlap, suggesting a defined autosomal recessive syndrome caused by reduced function of PTPN23. Shared characteristics of affected individuals include developmental delay, brain abnormalities (mainly ventriculomegaly and/or brain atrophy), intellectual disability, spasticity, language disorder, microcephaly, optic atrophy, and seizures. We observe a broad range of variants across patients that are likely strongly reducing the expression or disrupting the function of the protein. However, we do not observe any patients with an allele combination predicted to result in complete loss of function of PTPN23, as this is likely incompatible with life, consistent with reported embryonic lethality in the mouse. None of the observed or reported variants are recurrent, although some have been identified in homozygosis in patients from consanguineous populations. This study expands the phenotypic and molecular spectrum of PTPN23 associated disease and identifies major shared features among patients affected with this disorder, while providing additional support to the important role of PTPN23 in human nervous and visual system development and function.
Published: 2019
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28. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

Author: Francisca Millan, Mieke M. van Haelst, Ankita Patel, Cédric Le Caignec, Jean P. Pfotenhauer, Wendy E. Smith, Denise Horn, Klaske D. Lichtenbelt, Tanner Hagelstrom, David A. Dyment, Ryan J. Taft, Jill V. Hunter, Jolanta Wierzba, Margarita Saenz, Ian D. Krantz, Denise L. Perry, Luis F. Escobar, Bertrand Isidor, Ingrid Cristian, Richard E. Person, Aditi Chawla, Michael D. Fountain, Diane Masser-Frye, Sarah E. Raible, Koen L.I. van Gassen, Erin Torti, Weimin Bi, Philip J. Lupo, Jill A. Rosenfeld, Chumei Li, Claude Férec, Robert C. Pedersen, Megan E. Rech, Fan Xia, Sébastien Küry, Ilaria Parenti, Ingrid M. Wentzensen, Loren D M Pena, Jane Juusola, Manuel Holtgrewe, Frank J. Kaiser, John M. McCarthy, David S. Oleson, Arnold Munnich, Kévin Uguen, Thomas M. Morgan, Lara Segebrecht, Sung Hae L. Kang, Nadja Ehmke, Sunita Venkateswaran, Christian P. Schaaf, Marilyn C. Jones, Tim M. Strom, Rocio Moran, Stéphane Bézieau, Rebecca C. Spillmann, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: speech delay, Autism Spectrum Disorder, Autism, Haploinsufficiency, Bioinformatics, Whole Exome Sequencing, white matter paucity, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, 2.1 Biological and endogenous factors, Genetics(clinical), Child, Genetics (clinical), Exome sequencing, Pediatric, Genetics & Heredity, 0303 health sciences, Genome, neurodevelopment, Nuclear Proteins, Phenotype, Hypotonia, ddc, 3. Good health, DNA-Binding Proteins, Mental Health, Autism spectrum disorder, Speech delay, Chromosome Deletion, medicine.symptom, Human, Adolescent, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Article, 03 medical and health sciences, Clinical Research, Usp7, Neurodevelopment, Speech Delay, White Matter Paucity, Corpus Callosum Thinning, Intellectual Disability, 030225 pediatrics, Behavioral and Social Science, Genetics, medicine, Humans, Language Development Disorders, Preschool, 030304 developmental biology, Problem Behavior, business.industry, corpus callosum thinning, Neurosciences, Proteins, Infant, Newborn, medicine.disease, Brain Disorders, Neurodevelopmental Disorders, USP7, Congenital Structural Anomalies, business
Abstract: Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.
Published: 2019
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29. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author: Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: CHROMATIN, Male, 0301 basic medicine, Autism, Sequence Homology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, 0302 clinical medicine, SCHIZOPHRENIA, Gene expression, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, de novo variants, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, biology, neurodevelopmental disorders, histone acetylation, Adaptor Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Biological Sciences, Prognosis, Phenotype, Chromatin, Mental Health, Histone, intellectual disability, Child, Preschool, Female, REGULATOR, congenital malformations, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], BRAIN-DEVELOPMENT, Adult, Adolescent, Histone acetyltransferase complex, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Deciphering Developmental Disorders study, autism spectrum disorder, KAT6B, RNAI SCREEN, Young Adult, 03 medical and health sciences, CAUSES Study, Rare Diseases, Intellectual Disability, Report, COFACTOR, medicine, RUBINSTEIN-TAYBI-SYNDROME, Humans, Amino Acid Sequence, Autistic Disorder, Preschool, Gene, Genetic Association Studies, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Signal Transducing, Neurosciences, Infant, medicine.disease, TRRAP, Brain Disorders, SELF-RENEWAL, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, biology.protein, Missense, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
Published: 2019
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30. Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders

Author: Ingrid M. Wentzensen, Patrick Dunn, Caleb Heid, Esperanza Font-Montgomery, Anna Chassevent, Solveig Heide, Vinod K. Misra, Leandra Folk, Wendy K. Chung, Alexandra Afenjar, Sandra Whalen, Suzanne M. Leal, Thomas Smol, Erin Torti, Kathleen Brown, Isabelle Schrauwen, Anushree Acharya, Magali Barth, Mayada Helal, Mélanie Rama, Thomas Courtin, Irma Järvelä, Maura R.Z. Ruzhnikov, Farouq Thabet, Boris Keren, Haluk Kavus, Kara Withrow, J. Austin Hamm, Elizabeth A. Normand, Mitch Cunningham, Constance Smith-Hicks, Camille Fallot, Fanggeng Zou, Abdul Nasir, Donald R. Love, Alban Ziegler, Columbia University Medical Center (CUMC), Columbia University [New York], The George Washington University (GW), University of Agriculture Faisalabad - UAF (PAKISTAN), GeneDx [Gaithersburg, MD, USA], Stanford University, CHU Lille, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de génétique médicale, University of Colorado Anschutz [Aurora], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Kennedy Krieger Institute [Baltimore], Johns Hopkins University School of Medicine [Baltimore], CHU Pitié-Salpêtrière [AP-HP], University of Missouri [Columbia] (Mizzou), University of Missouri System, Sidra Medicine [Doha, Qatar], Children's Hospital of Michigan, Central Michigan University (CMU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Irma Järvelä / Principal Investigator, Medicum, and Department of Medical and Clinical Genetics
Subjects: 0301 basic medicine, INTELLECTUAL DISABILITY, GENES, GENETICS, phenotype, [SDV]Life Sciences [q-bio], human genetics, Biology, VARIANTS, UBIQUITIN LIGASE, 03 medical and health sciences, 0302 clinical medicine, Genotype-phenotype distinction, Neurodevelopmental disorder, Intellectual disability, medicine, Missense mutation, Genetics (clinical), Genetics, Massive parallel sequencing, MUTATIONS, neurology, 1184 Genetics, developmental biology, physiology, medicine.disease, Penetrance, Human genetics, Hypotonia, 030104 developmental biology, NEDL2, genetic variation, 3111 Biomedicine, medicine.symptom, HECW2, 030217 neurology & neurosurgery
Abstract: BackgroundVariants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.MethodsMolecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder.ResultsWe identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.ConclusionWe provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.
Published: 2021
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31. CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum

Author: Fowzan S. Alkuraya, Eric J. Mallack, Ingrid M. Wentzensen, John Karl de Dios, Subhadra Ramanathan, Robin D. Clark, Alpa Sidhu, Mais Hashem, Valérie Cormier-Daire, Maya Chopra, Danita Velasco, Shenela Lakhani, Lois J. Starr, Emily Singh, Didier Lacombe, Karin Panzer, Chloe Whitton, Elizabeth E. Palmer, Vincent Michaud, Lance H. Rodan, Christoffer Nellåker, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Pediatrics, medicine.medical_specialty, Developmental delay, Intellectual disability, Nerve Tissue Proteins, 03 medical and health sciences, Epilepsy, Exon, 0302 clinical medicine, Atrophy, Neurodevelopmental disorder, Genetics, Medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Global developmental delay, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, Arthrogryposis, 0303 health sciences, business.industry, Facies, Genomics, Syndrome, medicine.disease, Rare diseases, 3. Good health, Phenotype, Neurodevelopmental Disorders, Child, Preschool, Mutation, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: We describe the clinical features of nine unrelated individuals with rare de novo missense or in-frame deletions/duplications within the « HX motif » of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral-pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication.
Published: 2021
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32. Author response for 'CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum'

Author: null Elizabeth E. Palmer, null Chloe Whitton, null Mais O. Hashem, null Robin D. Clark, null Subhadra Ramanathan, null Lois J. Starr, null Danita Velasco, null John Karl De Dios, null Emily Singh, null Valerie Cormier‐Daire, null Maya Chopra, null Lance H. Rodan, null Christoffer Nellaker, null Shenela Lakhani, null Eric J. Mallack, null Karin Panzer, null Alpa Sidhu, null Ingrid M. Wentzensen, null Didier Lacombe, null Vincent Michaud, and null Fowzan S. Alkuraya
Published: 2021
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33. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Author: Ian R. Berry, Martin R. Larsen, Ann M. Neumeyer, Lilian Bomme Ousager, Leah J. Rowe, Richard E. Person, Chanika Phornphutkul, David A. Koolen, Constance T. R. M. Stumpel, Konrad Platzer, Elizabeth J. Bhoj, Eric Chater-Diehl, Jason Bunn, Erika Leenders, Koen L.I. van Gassen, Joshua Charkow, Rosanna Weksberg, Ny Hoang, Roos Cuperus, Davor Lessel, Rolph Pfundt, Oana Caluseriu, Sarah J. Goodman, Leandra Folk, Fanggeng Zou, Michelle T. Siu, David Chitayat, Dmitrijs Rots, Jeroen R. Vermeulen, Shuxi Liu, Cheryl Cytrynbaum, Elin Tønne, Hein Brackel, Mareike Mertens, Jennifer Campbell, Jonathan B. Strober, Maja Hempel, Tjitske Kleefstra, Małgorzata J.M. Nowaczyk, Amy Crunk, Marta Pacio-Míguez, Fernando Santos-Simarro, Nicola Brunetti-Pierri, Christa de Geus, María Palomares-Bralo, Lisenka E.L.M. Vissers, Sander Pajusalu, Peter Kannu, Sanaa Choufani, Kristin Lindstrom, Margarita Saenz, Berkley Schmidt, Daniëlle G.M. Bosch, Han G. Brunner, Arie van Haeringen, Ellen van Binsbergen, Brianna Pruniski, Claudia A. L. Ruivenkamp, William G. Wilson, Servi J. C. Stevens, Susan Walker, Kristian Tveten, Zain Awamleh, Gerarda Cappuccio, Alexander J. M. Dingemans, Michael Kwint, Ebba Alkhunaizi, Jonas Denecke, Alyssa Ritter, Eric W. Klee, Bert B.A. de Vries, Jeske V.T. van Harssel, Stephen Meyn, A. Chantal Deden, Francisca Millan, Eva Morava, Ingrid M. Wentzensen, Anne Slavotinek, Stephen W. Scherer, Katrin Õunap, Tuula Rinne, Jessica A. Radley, Yili Xie, Thatjana Gardeitchik, Laura Schultz-Rogers, Karit Reinson, Ronald D. Cohn, Hui Yang, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: DA Klinische Genetica (5), Rots, Dmitrij, Chater-Diehl, Eric, Dingemans, Alexander J M, Goodman, Sarah J, Siu, Michelle T, Cytrynbaum, Cheryl, Choufani, Sanaa, Hoang, Ny, Walker, Susan, Awamleh, Zain, Charkow, Joshua, Meyn, Stephen, Pfundt, Rolph, Rinne, Tuula, Gardeitchik, Thatjana, de Vries, Bert B A, Deden, A Chantal, Leenders, Erika, Kwint, Michael, Stumpel, Constance T R M, Stevens, Servi J C, Vermeulen, Jeroen R, van Harssel, Jeske V T, Bosch, Danielle G M, van Gassen, Koen L I, van Binsbergen, Ellen, de Geus, Christa M, Brackel, Hein, Hempel, Maja, Lessel, Davor, Denecke, Jona, Slavotinek, Anne, Strober, Jonathan, Crunk, Amy, Folk, Leandra, Wentzensen, Ingrid M, Yang, Hui, Zou, Fanggeng, Millan, Francisca, Person, Richard, Xie, Yili, Liu, Shuxi, Ousager, Lilian B, Larsen, Martin, Schultz-Rogers, Laura, Morava, Eva, Klee, Eric W, Berry, Ian R, Campbell, Jennifer, Lindstrom, Kristin, Pruniski, Brianna, Neumeyer, Ann M, Radley, Jessica A, Phornphutkul, Chanika, Schmidt, Berkley, Wilson, William G, Õunap, Katrin, Reinson, Karit, Pajusalu, Sander, van Haeringen, Arie, Ruivenkamp, Claudia, Cuperus, Roo, Santos-Simarro, Fernando, Palomares-Bralo, María, Pacio-Míguez, Marta, Ritter, Alyssa, Bhoj, Elizabeth, Tønne, Elin, Tveten, Kristian, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Rowe, Leah, Bunn, Jason, Saenz, Margarita, Platzer, Konrad, Mertens, Mareike, Caluseriu, Oana, Nowaczyk, Małgorzata J M, Cohn, Ronald D, Kannu, Peter, Alkhunaizi, Ebba, Chitayat, David, Scherer, Stephen W, Brunner, Han G, Vissers, Lisenka E L M, Kleefstra, Tjitske, Koolen, David A, and Weksberg, Rosanna
Subjects: 0301 basic medicine, Heart Septal Defects, Ventricular, Male, DNA methylation signature, nonsense-mediated decay, speech delay, PROTEIN, 030105 genetics & heredity, PHENOTYPE, epigenomic, Medical and Health Sciences, Epigenesis, Genetic, Craniofacial Abnormalities, Cohort Studies, Neurodevelopmental disorder, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), Growth Disorders, Epigenomics, non-FLHS SRCAP-related NDD, Genetics, Adenosine Triphosphatases, Genetics & Heredity, neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], SOTOS-LIKE, Biological Sciences, SRCAP, Hypotonia, AT-HOOK, 3. Good health, Phenotype, Mental Health, intellectual disability, Speech delay, DNA methylation, Female, medicine.symptom, Abnormalities, Multiple, EXON 34, Intellectual and Developmental Disabilities (IDD), Locus (genetics), Biology, genotype-phenotype correlation, DIAGNOSIS, Article, 03 medical and health sciences, Genetic, Clinical Research, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Floating-Harbor syndrome, SPECTRUM, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MUTATIONS, Heart Septal Defects, Infant, Newborn, Ventricular, dNaM, Infant, DNA Methylation, medicine.disease, Newborn, neurodevelopmental disorder, GENE, Brain Disorders, 030104 developmental biology, Floating–Harbor syndrome, Case-Control Studies, Mutation, epigenomics, EPISIGNATURES, Epigenesis
Abstract: Contains fulltext : 234078.pdf (Publisher’s version ) (Open Access) Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
Published: 2021
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34. Delineating the genotypic and phenotypic spectrum of

Author: Anushree, Acharya, Haluk, Kavus, Patrick, Dunn, Abdul, Nasir, Leandra, Folk, Kara, Withrow, Ingrid M, Wentzensen, Maura R Z, Ruzhnikov, Camille, Fallot, Thomas, Smol, Mélanie, Rama, Kathleen, Brown, Sandra, Whalen, Alban, Ziegler, Magali, Barth, Anna, Chassevent, Constance, Smith-Hicks, Alexandra, Afenjar, Thomas, Courtin, Solveig, Heide, Esperanza, Font-Montgomery, Caleb, Heid, J Austin, Hamm, Donald R, Love, Farouq, Thabet, Vinod K, Misra, Mitch, Cunningham, Suzanne M, Leal, Irma, Jarvela, Elizabeth A, Normand, Fanggeng, Zou, Mayada, Helal, Boris, Keren, Erin, Torti, Wendy K, Chung, and Isabelle, Schrauwen
Subjects: Phenotype, Genotype, Neurodevelopmental Disorders, Seizures, Intellectual Disability, Ubiquitin-Protein Ligases, Humans, Muscle Hypotonia
Abstract: Variants inMolecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with aWe identified 13 novel missense variants inWe provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of
Published: 2021

35. Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

Author: Nicole Fleischer, Grace M. Anbouba, Vandana Shashi, Thomas Meitinger, Damara Ortiz, Sumedha Ghate, Caleb Bupp, Maria J. Guillen Sacoto, Tiana M. Scott, Juliane Winkelmann, Felix Distelmaier, Sarah R Green, Dirk Klee, Carolyn R Serbinski, Lea Velsher, Michael T. Zimmermann, Meriel McEntagart, Gretchen Parsons, Patrick Yap, Evan H. Baugh, David S. Wargowski, Juan C Del Rey Jimenez, Anne K Olsen, Amy Armstrong-Javors, Victoria Mok Siu, Andrew Green, Nikita R. Dsouza, Elisabeth Graf, Sumit Punj, Matias Wagner, Anna Cereda, Naomi Meeks, Barbro Stadheim, Kirsty McWalter, Ingrid M. Wentzensen, Bert Callewaert, Rhonda E. Schnur, Emily Lancaster, Laurie A. Demmer, G. Bradley Schaefer, Kristin Lindstrom, Maria Iascone, Gonzalo Alonso Ramos-Rivera, Loren D M Pena, Amber Begtrup, Richard E. Person, Harrison Moore, Ameni Kdissa, Eric W. Klee, Dana Mittag, Jana Švantnerová, Ingrid Bader, Theresa Brunet, Johannes A. Mayr, Michael Zech, Jennifer A. Sullivan, Margot A. Cousin, Katharina Mayerhanser, Dagmar Wieczorek, Ralitza H. Gavrilova, and Daryl A. Scott
Subjects: Male, Genotype, ACETYLATION, Autism Spectrum Disorder, Chromosomal Proteins, Non-Histone, autism, Biology, Pediatrics, Whole Exome Sequencing, Article, Frameshift mutation, Autism, Developmental Delay, Histone Acetylation, Msl3, X-linked, DOMAIN, Genes, X-Linked, MSL COMPLEX, Intellectual Disability, Intellectual disability, Exome Sequencing, medicine, Medicine and Health Sciences, Missense mutation, Humans, Exome, Genetics (clinical), Exome sequencing, MOF, Genetics, MSL3, MUTATIONS, TRANSCRIPTIONAL REGULATION, Macrocephaly, histone acetylation, Non-Histone, medicine.disease, ddc, Chromosomal Proteins, DNA-Binding Proteins, developmental delay, Phenotype, Genes, Autism spectrum disorder, Female, medicine.symptom, DECAY, DOSAGE COMPENSATION
Abstract: PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.
Published: 2021

36. NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism

Author: Kun Xia, Samantha Ayres, Amber Begtrup, Danielle Karlowicz, Raphael Bernier, Ahood Alsulaiman, Frédéric Bilan, Rebecca Hernan, Elena Savva, Fowzan S. Alkuraya, Ingrid M. Wentzensen, Mohammad A. Al-Muhaizea, Audrey Labalme, Sumit Punj, Jenny Meylan Merlini, Evan E. Eichler, Lucile Letienne-Cejudo, Alexia Boizot, Natasha J Brown, Emily Bryant, Senwei Tan, Wendy K. Chung, Bin Yu, Inken Dreyer, Maria J. Guillen Sacoto, Jieqiong Tan, Hilde Peeters, Xiangbin Jia, Inge Lore Ruiz-Arana, Brina Daniels, Elizabeth A. Sellars, Linda Pons, Jianjun Ou, Rujia Dai, Guodong Chen, Gaetan Lesca, Lindsay Rhodes, Anne chun-hui Tsai, Chao Chen, Marie T. McDonald, Linda Laux, Kendra Hoekzema, Hui Guo, Christina Fagerberg, Bradley Schaefer, Huidan Wu, Rhonda E. Schnur, Qiumeng Zhang, Federico Santoni, Qian Pan, Rose B. McGee, Lucia Bartoloni, Brigitte Gilbert-Dussardier, Zhengmao Hu, Charlotte Brasch-Andersen, Dhamidhu Eratne, Valerie Slegesky, and Lori A. Carpenter
Subjects: Male, Autism Spectrum Disorder, Gene Expression, Variable Expression, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Genotype-phenotype distinction, Pregnancy, Intellectual disability, Protein Isoforms, RNA, Small Interfering, Child, de novo variants, Genetics (clinical), Cerebral Cortex, Mice, Knockout, Neurons, 0303 health sciences, Learning Disabilities, Phenotype, Pedigree, Autism spectrum disorder, Female, Neuroglia, Adolescent, Genotype, autism spectrum disorder, genotype-phenotype correlation, Biology, Article, 03 medical and health sciences, Young Adult, Intellectual Disability, Genetics, medicine, Animals, Humans, Loss function, 030304 developmental biology, Adaptor Proteins, Signal Transducing, disruptive variant, medicine.disease, neurodevelopmental disorder, NCKAP1, HEK293 Cells, Mutation, Autism, Transcriptome, Neuroscience, 030217 neurology & neurosurgery
Abstract: NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.
Published: 2020
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37. Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance

Author: Ingrid M. Wentzensen, R. Colombo, L. Baker, L. Immken, T. Barbaro-Dieber, Cameron Mroske, Julie S. Cohen, H. Nagakura, Ali Fatemi, J.F. Reynolds, E.S. Jordan, Zöe Powis, Christopher Cunniff, M. T. Cho, Jennifer Burton, Kirsty McWalter, I. Petrik, Rebecca Willaert, Kevin R. Payne, Joseph H. Hersh, Robert Huether, K.A. Aleck, Karen W. Gripp, T. Stamper, K.D. Farwell Hagman, M.J. Guillen Sacoto, K.L. David, Alessandro Serretti, Sha Tang, Powis, Z., Farwell Hagman, K.D., Mroske, C., McWalter, K., Cohen, J.S., Colombo, R., Serretti, A., Fatemi, A., David, K.L., Reynolds, J., Immken, L., Nagakura, H., Cunniff, C.M., Payne, K., Barbaro-Dieber, T., Gripp, K.W., Baker, L., Stamper, T., Aleck, K.A., Jordan, E.S., Hersh, J.H., Burton, J., Wentzensen, I.M., Guillen Sacoto, M.J., Willaert, R., Cho, M.T., Petrik, I., Huether, R., and Tang, S.
Subjects: Adult, Male, 0301 basic medicine, Adolescent, Developmental Disabilities, Penetrance, Biology, Young Adult, 03 medical and health sciences, Genetic, Intellectual Disability, Exome Sequencing, Intellectual disability, Genetics, medicine, Humans, Global developmental delay, Child, Gene, Genetics (clinical), Exome sequencing, Sequence (medicine), Infant, SETD5, Methyltransferases, Middle Aged, Body Dysmorphic Disorders, medicine.disease, Phenotype, haploinsufficiency, 030104 developmental biology, Child, Preschool, Mutation, Female, Chromosomes, Human, Pair 3, Chromosome Deletion, Haploinsufficiency
Abstract: Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.
Published: 2018
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38. Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability

Author: Maria J. Guillen Sacoto, Hilary J. Vernon, Meron Azage, Leandros Boukas, Berivan Baskin, Gregory D. Bowman, Dmitriy Niyazov, Ingrid M. Wentzensen, Megan T. Cho, Hans T. Bjornsson, Erin Beaver, Christina A. Gurnett, Genay Pilarowski, Paul J. Benke, Livija Medne, Jennifer M. Heeley, Ian D. Krantz, Carolyn D. Applegate, and Lindsay B. Henderson
Subjects: 0301 basic medicine, Genetics, Mechanism (biology), Disease, Biology, medicine.disease, Bioinformatics, Phenotype, Chromatin, 03 medical and health sciences, 030104 developmental biology, medicine, Missense mutation, Autism, Epigenetics, Gene, Genetics (clinical)
Abstract: BackgroundThe list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism.ObjectivesTo explore whether variants in CHD1 are associated with a human phenotype.MethodsWe used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts.ResultsHere we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1.ConclusionsOur results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.
Published: 2017
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39. Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum

Author: Bruce D. Gelb, Shalini C. Reshmi, Andrea Ciolfi, Marialetizia Motta, Alessandro Bruselles, Simone Martinelli, Dorothy K. Grange, Larry Walsh, Elisabetta Flex, Martina Di Rocco, Carlos E. Prada, Koen L.I. van Gassen, Luca Pannone, Mariet W. Elting, Simone Pizzi, Eva H. Brilstra, Danielle Mouhlas, Wendy K. Chung, Michelle M. Morrow, Marco Seri, Christina Lißewski, Luigi Memo, Mythily Ganapathi, Lorenzo Stella, Francesca Piceci-Sparascio, Julia Brinkmann, Francesca Clementina Radio, Dennis Bartholomew, Bruno Dallapiccola, Katelyn Payne, Emanuele Bellacchio, Federica Tamburrino, Alessandro De Luca, Sara Álvarez, Marco Tartaglia, Mónica Martínez-García, Giuseppe Zampino, Ingrid M. Wentzensen, Laura Mazzanti, Giovanna Carpentieri, Ronald R. Waclaw, Alberto Fernández-Jaén, Martin Zenker, Francesca Pantaleoni, Serena Cecchetti, Cesare Rossi, Ashita Dave-Wala, Quinten Waisfisz, Stefania Boni, Gianfranco Bocchinfuso, Motta M., Pannone L., Pantaleoni F., Bocchinfuso G., Radio F.C., Cecchetti S., Ciolfi A., Di Rocco M., Elting M.W., Brilstra E.H., Boni S., Mazzanti L., Tamburrino F., Walsh L., Payne K., Fernandez-Jaen A., Ganapathi M., Chung W.K., Grange D.K., Dave-Wala A., Reshmi S.C., Bartholomew D.W., Mouhlas D., Carpentieri G., Bruselles A., Pizzi S., Bellacchio E., Piceci-Sparascio F., Lissewski C., Brinkmann J., Waclaw R.R., Waisfisz Q., van Gassen K., Wentzensen I.M., Morrow M.M., Alvarez S., Martinez-Garcia M., De Luca A., Memo L., Zampino G., Rossi C., Seri M., Gelb B.D., Zenker M., Dallapiccola B., Stella L., Prada C.E., Martinelli S., Flex E., Tartaglia M., Human genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, MAPK/ERK pathway, Male, Carcinogenesis, Protein Tyrosine Phosphatase, Non-Receptor Type 11, MAPK cascade, Whole Exome Sequencing, ERK2, 0302 clinical medicine, Settore CHIM/02, Neurodevelopmental Disorder, MAPK1, Child, Genetics (clinical), Carcinogenesi, Mitogen-Activated Protein Kinase 1, Kinase, RSK, Noonan Syndrome, Cáncer, Noxas, Cell biology, Oncología médica, Phenotype, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, 030220 oncology & carcinogenesis, Child, Preschool, C. elegans, Female, Signal transduction, Human, Signal Transduction, Carcinogénesis, MAP Kinase Signaling System, Mutation, Missense, Biology, RASopathy, Non-Receptor Type 11, Article, 03 medical and health sciences, C. elegan, RASopathie, Exome Sequencing, Genetics, medicine, Humans, Protein kinase A, Preschool, RASopathies, Biología celular, intracellular signaling, RAS signaling, medicine.disease, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, ras Proteins, Noonan syndrome, Protein Tyrosine Phosphatase, Missense, MKP3
Abstract: Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies. Sin financiación 11.025 JCR (2020) Q1, 11/176 Genetics & Heredity 6.661 SJR (2020) Q1, 11/340 Genetics No data IDR 2020 UEM
Published: 2020
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40. MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis

Author: Géraldine Viot, Sara Halbach, Sandra Yang, William T. Gibson, Megan T. Cho, Sabine Luettgen, Pierre-Marie Martin, Karen W. Gripp, Christopher T. Gordon, Michael J. Bamshad, Jonas Denecke, Benjamin Apple, Thierry Bienvenu, William B. Dobyns, Elizabeth Francisco, Jill R. Murrell, Deborah A. Nickerson, Nadja Ehmke, Angela E. Lin, Kelly Radtke, Lisenka E.L.M. Vissers, Shelagh Joss, Farah R. Zahir, Louise Amlie-Wolf, Francisca Millan, Joan M. Stoler, Michael Parker, Youngha Lee, Carey McDougall, Denise Horn, Ruth McGowan, Elaine H. Zackai, Nicolas Lebrun, Ingrid M. Wentzensen, Zöe Powis, Oliver Puk, Nancy Vegas, Dan Doherty, Noa Lev-El, Amanda Barone Pritchard, Joseph T. Shieh, Francesca Filippini, Mariëtte J.V. Hoffer, Russell R. Reid, Valérie Cormier-Daire, Murim Choi, Michele G. Mehaffey, Stanislas Lyonnet, Jan M. Friedman, Sarina G. Kant, Yuri A. Zarate, David Viskochil, Gordon K.C. Leung, Angela M. Kaindl, Steven L.C. Pei, Christopher C.Y. Mak, Clémantine Dimartino, Koenraad Devriendt, Tiong Yang Tan, Mullin H.C. Yu, Chumei Li, Brian H.Y. Chung, Tim M. Strom, Lindsay B. Henderson, Elliot S. Stolerman, Trevor L Hoffman, Lina Basel-Salmon, Davor Lessel, Chelsea Roadhouse, Gisele E. Ishak, Caitlin Troyer, Jong-Hee Chae, Claudia Gonzaga-Jauregui, Ann Seman, Naama Orenstein, Marcie A. Steeves, Eric G. Bend, James D. Weisfeld-Adams, Jamel Chelly, William G. Wilson, Jeanne Amiel, and Darrel Waggoner
Subjects: 0301 basic medicine, Proband, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, Intellectual disability, medicine, Craniofacial, Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MN1, rhombencephalosynapsis, Original Articles, Perisylvian polymicrogyria, medicine.disease, craniofacial development, MCTT syndrome, 030104 developmental biology, medicine.anatomical_structure, intellectual disability, Cerebellar vermis, Trigeminal artery, Neurology (clinical), Haploinsufficiency, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 218289.pdf (Publisher’s version ) (Closed access) MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
Published: 2020

41. Genetic evaluation including exome sequencing of two patients with Gomez-Lopez-Hernandez syndrome: Case reports and review of the literature

Author: Ingrid M. Wentzensen, Cathy A. Stevens, David Suhrbier, Faith Lindsay, and Ilse J. Anderson
Subjects: Proband, Male, Pediatrics, medicine.medical_specialty, Adolescent, Craniofacial Abnormalities, Gomez Lopez Hernandez syndrome, Cerebellum, Intellectual disability, Gene duplication, Exome Sequencing, Genetics, medicine, Humans, Clinical significance, Abnormalities, Multiple, Exome, Hypertelorism, Genetics (clinical), Exome sequencing, Growth Disorders, business.industry, Neurocutaneous Syndromes, Genetic disorder, Alopecia, medicine.disease, Rhombencephalon, Phenotype, Female, medicine.symptom, business
Abstract: Rhombencephalosynapsis (RES) is a rare congenital anomaly of the hindbrain characterized by fusion of the cerebellar hemispheres, cerebellar peduncles, and dentate nuclei with vermian absence or hypogenesis. This anomaly can be isolated or part of a larger spectrum of cerebral abnormalities. At least 90 cases are described in the literature and it has been associated with VACTERL and Gomez-Lopez-Hernandez syndrome (GLHS). The most common congenital syndrome associated with RES is GLHS, a rare presumed genetic disorder with over 30 cases thus far described in the literature. No genetic cause has been identified for RES or GLHS. We report two probands diagnosed with GLHS based on clinical criteria. Each proband had RES and bi-parietal scalp alopecia as well as neurologic findings and phenotypic features including trigeminal anesthesia, borderline hypertelorism, midface retrusion, and motor delay. Oliginucleotide-SNP microarray on the male proband revealed a 1.05 Mb copy duplication of uncertain clinical significance at 15q21.3 while oligonucleotide-SNP microarray for the female proband did not reveal any abnormalities. Exome sequencing (ES) was performed on both patients and did not identify any variants that could explain the GLHS phenotype. To our knowledge, these are the first two patients with GLHS described in the literature to undergo ES. Both patients had mild neurologic manifestations requiring physical therapy in early life without known diagnostic cause. Patients found to have scalp alopecia or trigeminal anesthesia with gross motor delay should be evaluated for RES or GLHS as well as screened for associated syndromes and have a complete neurodevelopmental evaluation.
Published: 2019

42. 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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43. Novel KIAA1033/WASHC4 mutations in three patients with syndromic intellectual disability and a review of the literature

Author: Melissa L. Crenshaw, Karin M. Dent, Ange Line Bruel, Mirna Assoum, Ingrid M. Wentzensen, Antonio Vitobello, Laurence Faivre, Kirsty McWalter, Paul Kuentz, Julian Delanne, Christel Thauvin-Robinet, Julien Thevenon, and Yannis Duffourd
Subjects: 0301 basic medicine, Adult, Male, Microcephaly, 030105 genetics & heredity, Compound heterozygosity, Short stature, 03 medical and health sciences, KIAA0196, Intellectual Disability, Intellectual disability, Genetics, Medicine, Missense mutation, Humans, Genetics (clinical), Exome sequencing, business.industry, Macrocephaly, Infant, Newborn, Intracellular Signaling Peptides and Proteins, medicine.disease, Pedigree, Protein Subunits, 030104 developmental biology, Phenotype, Child, Preschool, Mutation, Female, medicine.symptom, business
Abstract: In 2011, KIAA1033/WASHC4 was associated with autosomal recessive intellectual disability (ARID) in a large consanguineous family comprising seven affected individuals with moderate ID and short stature. Since then, no other cases of KIAA1033 variants have been reported. Here we describe three additional patients (from two unrelated families) with syndromic ID due to compound heterozygous KIAA1033 variants ascertained by exome sequencing (ES). Two sisters, aged 4 and 5.5 years, had a stop-gain and a missense variants, each inherited from one parent (p.(Gln442*) and p.(Asp1048Gly)). Both had learning disabilities, macrocephaly, dysmorphic features, skeletal anomalies, and subependymal heterotopic nodules. In addition, the younger sibling had a congenital absence of the right internal carotid and bilateral sensorineural hearing loss. The third patient was aged 34 years and had two missense variants, one inherited from each parent (p.(Lys1079Arg) and p.(His503Arg)). This patient presented with mild ID, short stature, and microcephaly. KIAA1033 encodes a large protein (WASHC4), which is part of the WASH complex. The WASH complex is involved in the regulation of the fission of tubules that serve as transport intermediates during endosome sorting. Another member of the WASH complex, KIAA0196/WASHC5, has already been implicated in ARID with brain and cardiac malformations, under the designation of 3C or Ritscher-Schinzel syndrome (MIM#20210). ES has proved efficient for finding replications of genes with insufficient data in the literature to be defined as new OMIM genes. We conclude that KIAA1033 is responsible for a heterogeneous ARID phenotype, and additional description will be needed to refine the clinical phenotype.
Published: 2019

44. Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder

Author: Rolph Pfundt, Christel Depienne, Bregje W.M. van Bon, Gregory M. Cooper, David E. Gray, Kirsty McWalter, James M.J. Lawlor, Tuula Rinne, Louisa Kalsner, Pascal Joset, Jeremy W. Prokop, Susan M. Hiatt, Ruxandra Bachmann-Gagescu, Marlies Kempers, Cyril Mignot, E. Martina Bebin, Michelle L. Thompson, Ingrid M. Wentzensen, Caroline Nava, Anita Rauch, University of Zurich, and Cooper, Gregory M
Subjects: 0301 basic medicine, Proband, Male, 10039 Institute of Medical Genetics, Developmental Disabilities, Medizin, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Exome, Child, Genetics (clinical), Exome sequencing, Genetics, Motor Skills Disorders, Phenotype, Child, Preschool, Speech delay, Female, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 2716 Genetics (clinical), Heterozygote, Adolescent, 610 Medicine & health, Child Behavior Disorders, Biology, Protein Serine-Threonine Kinases, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, 1311 Genetics, Report, Intellectual Disability, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Autistic Disorder, Loss function, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic Variation, medicine.disease, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, Autism, 570 Life sciences, biology, 030217 neurology & neurosurgery, Gene Deletion
Abstract: Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the remaining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p = 2.46 × 10(−6)). We also find that exome sequencing provides lower coverage and appears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2’s visibility in many clinical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease.
Published: 2019

45. Am J Hum Genet

Author: Robert Smigiel, Géraldine Joly-Helas, Linyan Meng, Gregory M. Cooper, Nolwenn Jean-Marçais, Christel Thauvin-Robinet, Bruno Kieffer, Christopher T. Gordon, Laurence Faivre, Rhonda E. Schnur, Sarah L. Dugan, Seema R. Lalani, Heather C Mefford, Susan M. Hiatt, Marlène Rio, Seiamak Bahram, Jamel Chelly, Caroline Schluth-Bolard, Tatiana Tvrdik, Alison M. Muir, Eva Erdmann, Aline Kolmer, Aurore Garde, Angélique Pichot, Raphael Carapito, Mary K. Kukolich, Andrea M. Lewis, David Hunt, Clémantine Dimartino, Aurore Morlon, Anne Molitor, Ingrid M. Wentzensen, Fabien Dutreux, Nicodème Paul, Carlos A. Bacino, Nina B. Gold, Frédéric Tran Mau-Them, Olaf Bodamer, Deciphering Developmental Disorders Study, Zijie Sun, Pinar Bayrak-Toydemir, Heather P. Crawford, Victoria Harrison, Jocelyn Céraline, Jeanne Amiel, Mira Kharbanda, Christina Hung, A. Hanauer, Anne-Marie Guerrot, David Viskochil, Bertrand Isidor, Maya Chopra, Kirsty McWalter, Lydie Naegely, Meredith Phillips, Xia Wang, Rafał Płoski, Noel Mensah-Bonsu, Ekaterina L. Ivanova, Magalie S. Leduc, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Developmental Disabilities, Aucun, Biology, 030226 pharmacology & pharmacy, Transactivation, 03 medical and health sciences, Mice, Neurodevelopmental disorder, 0302 clinical medicine, Report, Intellectual Disability, Coactivator, medicine, Genetics, Animals, Humans, Point Mutation, Allele, Child, Exome, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, Point mutation, Correction, Infant, Syndrome, medicine.disease, Androgen receptor, 030104 developmental biology, Child, Preschool, Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract: ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.
Published: 2019
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46. Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation

Author: Chris Balak, Hélène Dollfus, Sumaiya Iqbal, Newell Belnap, Kristin G. Monaghan, Lorida Llaci, Sampathkumar Rangasamy, Véronique Geoffroy, Jean-Louis Mandel, Dennis Lal, Jamel Chelly, Keri Ramsey, Maïté Courel, Kirsty McWalter, Ignazio S. Piras, Marcus Naymik, Rolph Pfundt, Michèle Ernoult-Lange, Wayne M. Jepsen, Vinodh Narayanan, Antony Le Béchec, Dominique Weil, Kristine K. Bachman, Ryan Richholt, Szabolcs Szelinger, Matthew J. Huentelman, Johanna ter Beest, Arthur Campbell, Ingrid M. Wentzensen, Francesca Mattioli, Marianne Bénard, Jean Muller, Jean-François Deleuze, Amélie Piton, Anne Boland, Elise Schaefer, Patrick Rump, Matt De Both, Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Center [Nijmegen], GeneDx [Gaithersburg, MD, USA], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Les Hôpitaux Universitaires de Strasbourg (HUS), Cologne Center for Genomics, University of Cologne, Laboratoire de Biologie du Développement [IBPS] (LBD), weil, dominique, The Translational Genomics Research Institute (TGen), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), University of Groningen [Groningen], Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CEA- Saclay (CEA), Lerner Research Institute [Cleveland, OH, USA], Cleveland Clinic, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement (LBD), Service de Génétique, Hôpital de Hautepierre [Strasbourg], Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CDF (laboratoire)), Collège de France (CdF (institution)), and Bénard, Marianne
Subjects: [SDV]Life Sciences [q-bio], RecA domain, DENDRITES, DEAD-box RNA Helicases, 0302 clinical medicine, Missense mutation, NEURONS, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, DEAD-box, RNA Helicase A, [SDV] Life Sciences [q-bio], helicase, intellectual disability, missense variants, DDX3X, COMMON-CAUSE, mRNA metabolism, RNA helicase, processing bodies, DEAD box, PROTEINS, Mutation, Missense, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, METABOLISM, Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Proto-Oncogene Proteins, DDX6, TRANSLATIONAL REPRESSION, REVEALS, Humans, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Messenger RNA, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, MUTATIONS, Helicase, RNA, DExD/H-box, FRAMEWORK, neurodevelopmental disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, p-bodies, biology.protein, 030217 neurology & neurosurgery
Abstract: International audience; The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.
Published: 2019
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47. Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons

Author: Jacques L. Michaud, Jessica Sebastian, Hanrong Wu, Dick Lindhout, Karla Manzano-Vargas, Nuwan C. Hettige, Ingrid M. Wentzensen, Huashan Peng, Amy Crunk, Heika Silviera, Malvin Jefri, Henry Houlden, Fadi F. Hamdan, Zahia Aouabed, Stephanie Efthymiou, Xin Zhang, Renske Oegema, Arnaud Tanti, Jerry Vockley, Gustavo Turecki, Julien van Gils, Amber G. Begtrup, Christina Nassif, Gunnar Houge, Naomichi Matsumoto, Thomas Bourgeron, Jean-François Théroux, Emily Fassi, Noriko Miyake, Robert D. Nicholls, Jose E. Martinez, Kristin Herman, Lilit Antonyan, Philippe M. Campeau, Margaret G. Au, Dominic Nelson, Vincenzo Salpietro, Scott C. Bell, Pierre Priam, Joshua L. Deignan, Gregory M. Cooper, Rune Østern, Han G. Brunner, Dagmar Huhle, Amy Goldstein, John M. Graham, Christine Coubes, Koen L.I. van Gassen, Tabib Dabir, Maria Hafström, Simon Gravel, Sophie Ehresmann, Elsa Rossignol, Ilaria Kolobova, Walla Al-Hertani, Julie A. Lessard, Lionel Carmant, Sonja Martin, Richard Delorme, Carl Ernst, Jolien S. Klein Wassink-Ruiter, Naguib Mechawar, Yoshio Makita, Candice R. Finnila, Rami Abou Jamra, Anne Lortie, Justine Rousseau, Sarju G. Mehta, Lina Ghaloul-Gonzalez, MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, McGill University = Université McGill [Montréal, Canada], Université de Montréal (UdeM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), GeneDx [Gaithersburg, MD, USA], University of California [Davis] (UC Davis), University of California, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Calgary, UCL, Institute of Neurology [London], Yokohama City University (YCU), Asahikawa Medical College, Trondheim University, Haukeland University Hospital, University of Bergen (UiB), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University of Groningen [Groningen], University Medical Center Groningen [Groningen] (UMCG), Children's Hospital of Pittsburgh of UPMC [Etats-Unis], Belfast City Hospital, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HudsonAlpha Institute for Biotechnology [Huntsville, AL], Children’s Rehabilitation Service [Mobile, AL] (CRS), Children's Rehabilitation Service [Montgomery, AL] (CRS), University Medical Center [Utrecht], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), University Hospital Leipzig, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Cedars-Sinai Medical Center, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), We acknowledge funding by FRQS doctoral (S.B.), Indonesian Endowment Fund for Education PhD award (M.J.), CONACYT (Mexico) and MITACS (K.M.V.), Genome Canada and Génome Québec (J.L.M. and E.R.), Canada Research Chairs program (G.T. and C.E.), AMED, MEXT, JST, MHLW, and Takeda Science Foundation (N. Matsumoto), and CIHR grant (C.E. and P.M.C.)., University of California (UC), University of California (UC)-University of California (UC), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Radboud University [Nijmegen], and Faculteit Medische Wetenschappen/UMCG
Subjects: 0301 basic medicine, Male, PROTEIN EXPRESSION, Chromosomal Proteins, Non-Histone, Mutant, MESH: Neurons, 0302 clinical medicine, SYNAPTIC PLASTICITY, MESH: Child, Genetics(clinical), Global developmental delay, TRANSCRIPTION, Child, Genetics (clinical), ACTL6B, genetic engineering, intellectual disability, neurodevelopment, seizure, stem cells, Genetics, Neurons, SWI/SNF COMPLEX, MESH: Infant, Hypotonia, Neural stem cell, Chromatin, DNA-Binding Proteins, medicine.anatomical_structure, MESH: Young Adult, MESH: Epilepsy, Child, Preschool, Female, medicine.symptom, Adult, MESH: Mutation, DISORDERS, Induced Pluripotent Stem Cells, Biology, MESH: Induced Pluripotent Stem Cells, MESH: Actins, MESH: Dendrites, Chromatin remodeling, Article, MESH: Chromatin, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, MESH: Chromosomal Proteins, Non-Histone, medicine, Journal Article, Humans, CHROMATIN REMODELING COMPLEX, Progenitor cell, Loss function, MESH: Neurodevelopmental Disorders, MESH: Humans, Epilepsy, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Child, Preschool, COFFIN-SIRIS SYNDROME, MEMORY, Infant, MESH: Adult, Dendrites, GENE, MESH: Male, Actins, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, OLIGODENDROCYTE, Neuron, MESH: Female, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract: International audience; We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.
Published: 2019
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48. De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

Author: Patricia G Wheeler, Anya Revah-Politi, Viktor Stranecky, Alejandro Iglesias, James W. Wheless, Anna C.E. Hurst, Nicholas Stong, Parisa Hemati, Ryne C. Ramaker, Zdenek Sedlacek, Caroline Nava, Matthew B. Neu, Yves Lacassie, Cyril Mignot, Jan Prchal, Richard M. Myers, Marketa Havlovicova, Jeremy W. Prokop, Darina Prchalova, Rebecca Willaert, Zöe Powis, Susan M. Hiatt, Dwight K. C. Yim, Mariya Kozenko, Andrew A. Hardigan, Gregory M. Cooper, Lauren Brick, Boris Keren, Sharon F. Suchy, Miroslava Hancarova, Ingrid M. Wentzensen, Gregory S. Barsh, and Marlène Rio
Subjects: 0301 basic medicine, Proband, Models, Molecular, Cancer Research, Mutation rate, GTP', Protein Conformation, Hydrolases, Developmental Disabilities, Glycobiology, GTPase, QH426-470, medicine.disease_cause, Biochemistry, Database and Informatics Methods, 0302 clinical medicine, Medicine and Health Sciences, Missense mutation, Small GTPase, Public and Occupational Health, Genome Sequencing, Enzyme-Linked Immunoassays, Child, Genetics (clinical), Genetics, education.field_of_study, Mutation, 0303 health sciences, Guanosine, Nucleosides, Phenotype, RALA, Glycosylamines, Recombinant Proteins, Enzymes, Phenotypes, Bioassays and Physiological Analysis, Developmental disabilities--Genetic aspects, Perspective, Metabolic Pathways, Guanosine Triphosphate, Anatomy, Sequence Analysis, Research Article, Signal Transduction, Genotype, Bioinformatics, Disabilities, Population, Mutation, Missense, Biology, Research and Analysis Methods, Guanosine Diphosphate, Mitochondrial Proteins, 03 medical and health sciences, Amino Acid Sequence Analysis, Intellectual Disability, medicine, Humans, Protein Interaction Domains and Motifs, Allele, education, Immunoassays, Molecular Biology Techniques, Sequencing Techniques, Gene, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Alleles, 030304 developmental biology, Enzyme Assays, Facies, Biology and Life Sciences, Proteins, Human Genetics, Guanosine Triphosphatase, 030104 developmental biology, Metabolism, Genetic Loci, FOS: Biological sciences, Face, Genetics of Disease, ras Proteins, Immunologic Techniques, Enzymology, ral GTP-Binding Proteins, Biochemical Analysis, Head, 030217 neurology & neurosurgery
Abstract: Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10−11) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases., Author summary While many causes of developmental disabilities have been identified, a large number of affected children cannot be diagnosed despite extensive medical testing. Previously unknown genetic factors are likely to be the culprits in many of these cases. Using DNA sequencing, and by sharing information among many doctors and researchers, we have identified a set of individuals with developmental problems who all have changes to the same gene, RALA. The affected individuals all have similar symptoms, including intellectual disability, speech delay (or no speech), and problems with motor skills like walking. In nearly all of these cases (10 of 11), the genetic change found in the child was not inherited from either parent. The locations and biological properties of these changes suggest that they are likely to disrupt the normal functions of RALA. Functional experiments also show that the genetic changes found in these individuals alter two key functions of RALA. Together, we have provided evidence that genetic changes in RALA can cause developmental disabilities. These results will allow doctors and researchers to identify additional children with the same condition, providing a clinical diagnosis to these families and leading to new research opportunities.
Published: 2018

49. Additional de novo missense genetic variants in NALCN associated with CLIFAHDD syndrome

Author: Katelyn Payne, K. Mason, S. Debrosse, Megan T. Cho, Wendy K. Chung, Ingrid M. Wentzensen, Jane Juusola, Amber Begtrup, M. Vivero, Yuri A. Zarate, G B Schaefer, Kyle Retterer, K. Bosanko, L. Pollack, S. Deward, and Larry Walsh
Subjects: 0301 basic medicine, Genetics, 03 medical and health sciences, 030104 developmental biology, Neurodevelopmental disorder, medicine, Genetic variants, Missense mutation, Biology, medicine.disease, Genetics (clinical), Exome sequencing
Published: 2017
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50. Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures

Author: M.J. Guillen Sacoto, Kyle Retterer, Rashmi Chikarmane, Berivan Baskin, Barbara K. Burton, Emma Bedoukian, S Hopkins, Brooke E. Spangler, Heather M. McLaughlin, Wendy K. Chung, Fran Kendall, Matthew A. Deardorff, David Kronn, M. T. Cho, Marie T. McDonald, Rebecca Willaert, N Oundjian, D Stern, Ingrid M. Wentzensen, Anne Slavotinek, Dianalee McKnight, Allyn McConkie-Rosell, S Schrier Vergano, Katherine H. Kim, and N Chandy
Subjects: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Electroencephalography, behavioral disciplines and activities, 03 medical and health sciences, Internal medicine, mental disorders, Intellectual disability, Genetics, medicine, Attention deficit hyperactivity disorder, Missense mutation, cardiovascular diseases, Association (psychology), Genetics (clinical), medicine.diagnostic_test, business.industry, Fontanelle, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Cardiology, Patent foramen ovale, business, psychological phenomena and processes, Patent ductus arteriosis
Abstract: Graphical abstract key: ADHD, attention deficit hyperactivity disorder; ASD, atrial septal defect; DD, developmental delay; EEG, electroencephalogram; Ht, height; ID, intellectual disability; OCD, obsessive-compulsive disorder; OFC, open fontanelle; PDA, patent ductus arteriosis; PFO, patent foramen ovale; VSD, ventricular septal defect; Wt, weight.
Published: 2017
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