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Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome
Authors:Jet van der Spek  Joery den Hoed  Lot Snijders Blok  Alexander JM Dingemans  Dick Schijven  Christoffer Nellaker  Hanka Venselaar  Galuh DN Astuti  Tahsin Stefan Barakat  E Martina Bebin  Stefanie Beck-Wödl  Gea Beunders  Natasha J Brown  Theresa Brunet  Han G Brunner  Philippe M Campeau  Goran ?uturilo  Christian Gilissen  Tjitske Kleefstra
Institution:1. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;2. Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands;3. Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands;4. International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands;5. Nuffield Department of Women’s and Reproductive Health, University of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford, United Kingdom;6. Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom;7. Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom;8. Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands;9. Division of Human Genetics, Center for Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University, Semarang, Indonesia;10. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands;11. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL;12. Department of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany;13. Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands;14. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville, Victoria, Australia;15. Department of Pediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, Victoria, Australia;16. Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany;17. Department of Clinical Genetics, Maastricht University Medical Center, GROW School for Oncology and Developmental Biology, and MHeNS School for Mental health and Neuroscience, Maastricht University, Maastricht, The Netherlands;18. CHU Sainte-Justine Research Center, Montreal, Quebec, Canada;19. Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada;20. University Children’s Hospital Belgrade, Belgrade, Serbia;21. Faculty of Medicine, University of Belgrade, Belgrade, Serbia;22. Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands;23. Institute of Human Genetics, University of Lübeck, Lübeck, Germany;24. Department of Neuropediatrics, Jena University Hospital, Jena, Germany;25. Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia;26. Clinical Institute for Genomic Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia;27. Department of Neuropaediatrics, Developmental Neurology, Social Pediatrics, University Children’s Hospital, University of Tübingen, Tübingen, Germany;28. Department of Pediatrics, Naval Medical Center Portsmouth, Portsmouth, VA;29. Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA;30. INSMC Alessandrescu-Rusescu, Regional Center of Medical Genetics Bucharest, Bucharest, Romania;31. Genetic Health Queensland, Royal Brisbane and Women’s hospital, Herston, Queensland, Australia;32. School of Medicine, Griffith University, Southport, Queensland, Australia;33. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany;34. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;35. Praxis für Humangenetik-Bremen, Bremen, Germany;36. HudsonAlpha Institute for Biotechnology, Huntsville, AL;37. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands;38. Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands;1. Division of Genetics & Genomics and the Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA;2. Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY;3. Genomic Medicine Institute, Geisinger, Danville, PA;4. Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, and College of Medicine, University of Cincinnati, Cincinnati, OH;5. Genetic Services, Kaiser Permanente of Washington, Seattle, WA;6. Center for Biomedical Ethics and Society and Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN;7. Division of Genetic Medicine, Department of Medicine, and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN;8. Department of Pediatrics, Harvard Medical School, Boston, MA;1. Institute for Human Genetics, University of California San Francisco, San Francisco, CA;2. Institute for Health & Aging, School of Nursing, University of California San Francisco, San Francisco, CA;3. Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, San Francisco, CA;4. Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA;5. Department of Social & Behavioral Sciences, School of Nursing, University of California San Francisco, San Francisco, CA;1. Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;3. Faculty of Health Sciences, Ben Gurion University of the Negev, Be’er Sheva, Israel;4. Genetic Institute, Soroka University Medical Center, Be’er Sheva, Israel;5. Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;1. Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL;2. Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL;1. The Department of Pediatrics, School of Medicine & Health Sciences, The George Washington University, Washington, DC;2. Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL;3. Department of Research, The Focus Foundation, Davidsonville, MD;4. Pediatric Endocrinology, The Herman & Walter Samuelson Children''s Hospital, Baltimore, MD;5. Department of Economics, Columbian College of Arts and Science, The George Washington University, Washington, DC;6. Department of Neurology & Rehabilitation Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC;7. Division of Neurodevelopmental Pediatrics & Neurogenetics, Children’s National Health System, Washington, DC;1. Cancer Prevention and Control Platform, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, TX;2. Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX;3. Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX;4. Research Medical Library, The University of Texas MD Anderson Cancer Center, Houston, TX
Abstract:PurposeCommon diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed.MethodsWe characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome.ResultsComputational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted.ConclusionOur results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease.
Keywords:CHD3  Inherited variants  Neurodevelopmental disorder  Reduced penetrance  Variable expressivity
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