Paul A Wade1, Katherine Lachlan2, Karin Weiss3, Hayley P Lazar1, Alina Kurolap4,5, Ariel F Martinez6, Tamar Paperna4, Lior Cohen7, Marie F Smeland8, Sandra Whalen9, Solveig Heide10, Boris Keren10, Pauline Terhal11, Melita Irving12, Motoki Takaku1, John D Roberts1, Robert M Petrovich1, Samantha A Schrier Vergano13,14, Amy Kenney13, Hanne Hove15, Elizabeth DeChene16, Shane C Quinonez17, Estelle Colin18, Alban Ziegler18, Melissa Rumple19, Mahim Jain6,20, Danielle Monteil21, Elizabeth R Roeder22, Kimberly Nugent22, Arie van Haeringen23, Michael Gambello24, Avni Santani16, Līvija Medne25, Bryan Krock16, Cara M Skraban25, Elaine H Zackai25, Holly A Dubbs26, Thomas Smol27,28, Jamal Ghoumid27,28, Michael J Parker29, Michael Wright30, Peter Turnpenny31, Jill Clayton-Smith32,33, Kay Metcalfe32,33, Hitoshi Kurumizaka34, Bruce D Gelb35, Hagit Baris Feldman4,5, Philippe M Campeau36, Maximilian Muenke6. 1. Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. 2. Wessex Clinical Genetics Service, University Hospital Southampton NHS Trust. Department of Human Genetics and Genomic Medicine, Southampton University, Southampton, UK. 3. The Genetics Institute, Rambam Health Care Campus, Haifa, Israel. k_weiss@rambam.health.gov.il. 4. The Genetics Institute, Rambam Health Care Campus, Haifa, Israel. 5. The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 6. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. 7. Genetics Institute, Schneider Children's Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 8. Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway. 9. UF de génétique clinique, Centre de Référence Maladies Rares des Anomalies du développement et syndromes malformatifs, APHP, Hôpital Trousseau, Paris, France. 10. AP-HP, Département de Génétique, Centre de Référence Maladies Rares "Anomalies du développement et syndromes malformatifs" Hôpital de la Pitié Salpêtrière, Paris, France. 11. Department of Genetics, Utrecht University Medical Center, Utrecht, the Netherlands. 12. Department of Clinical Genetics, Guy's Hospital, London, UK. 13. Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA. 14. Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, USA. 15. Centre for Rare Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 16. Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 17. Department of Pediatrics, Division of Genetics, Metabolism and Genomic Medicine, University of Michigan, Ann Arbor, MI, USA. 18. Department of Biochemistry and Genetics, University Hospital Angers, Angers, France. 19. Banner Child Neurology, Glendale, AZ, USA. 20. Bone and Osteogenesis Imperfecta Department, Kennedy Krieger Institute, Baltimore, MD, USA. 21. Department of Pediatrics, Naval Medical Center Portsmouth, Portsmouth, VA, USA. 22. Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX, USA. 23. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 24. Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA. 25. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 26. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 27. Department of Clinical Genetics, Lille University Hospital, CHU Lille, Lille, France. 28. EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France. 29. Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, UK. 30. Northern Genetics Service, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK. 31. University of Exeter Medical School, Clinical Genetics Royal Devon & Exeter Hospital, Exeter, UK. 32. Institute of Evolution, Systems and Genomics, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. 33. Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK. 34. Laboratory of Structural Biology, Graduate School of Advanced Science & Engineering, Waseda University, Tokyo, Japan. 35. Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 36. Department of Pediatrics, University of Montreal and CHU Sainte-Justine, Montreal, QC, Canada.
Abstract
PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
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