Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

Jet van der Spek¹, Joery den Hoed², Lot Snijders Blok³, Alexander J M Dingemans¹, Dick Schijven⁴, Christoffer Nellaker⁵, Hanka Venselaar⁶, Galuh D N Astuti⁷, Tahsin Stefan Barakat⁸, E Martina Bebin⁹, Stefanie Beck-Wödl¹⁰, Gea Beunders¹¹, Natasha J Brown¹², Theresa Brunet¹³, Han G Brunner¹⁴, Philippe M Campeau¹⁵, Goran Čuturilo¹⁶, Christian Gilissen¹⁷, Tobias B Haack¹⁰, Irina Hüning¹⁸, Ralf A Husain¹⁹, Benjamin Kamien²⁰, Sze Chern Lim²¹, Luca Lovrecic²², Janine Magg²³, Ales Maver²², Valancy Miranda¹⁵, Danielle C Monteil²⁴, Charlotte W Ockeloen²⁵, Lynn S Pais²⁶, Vasilica Plaiasu²⁷, Laura Raiti²¹, Christopher Richmond²⁸, Angelika Rieß¹⁰, Eva M C Schwaibold²⁹, Marleen E H Simon³⁰, Stephanie Spranger³¹, Tiong Yang Tan¹², Michelle L Thompson³², Bert B A de Vries¹, Ella J Wilkins²¹, Marjolein H Willemsen²⁵, Clyde Francks³³, Lisenka E L M Vissers¹, Simon E Fisher³³, Tjitske Kleefstra³⁴

Affiliations

¹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
² Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
³ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
⁴ Department of Language and Genetics, 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; Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom.
⁶ Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁷ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Division of Human Genetics, Center for Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University, Semarang, Indonesia.
⁸ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁹ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL.
¹⁰ Department of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
¹¹ Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
¹² Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
¹³ Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany.
¹⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; 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.
¹⁵ CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada.
¹⁶ University Children's Hospital Belgrade, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
¹⁷ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁸ Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
¹⁹ Department of Neuropediatrics, Jena University Hospital, Jena, Germany.
²⁰ Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia.
²¹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
²² Clinical Institute for Genomic Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia.
²³ Department of Neuropaediatrics, Developmental Neurology, Social Pediatrics, University Children's Hospital, University of Tübingen, Tübingen, Germany.
²⁴ Department of Pediatrics, Naval Medical Center Portsmouth, Portsmouth, VA.
²⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁶ Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA.
²⁷ INSMC Alessandrescu-Rusescu, Regional Center of Medical Genetics Bucharest, Bucharest, Romania.
²⁸ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Genetic Health Queensland, Royal Brisbane and Women's hospital, Herston, Queensland, Australia; School of Medicine, Griffith University, Southport, Queensland, Australia.
²⁹ Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
³⁰ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
³¹ Praxis für Humangenetik-Bremen, Bremen, Germany.
³² HudsonAlpha Institute for Biotechnology, Huntsville, AL.
³³ Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands.
³⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands. Electronic address: Tjitske.Kleefstra@radboudumc.nl.

PMID: 35346573
DOI: 10.1016/j.gim.2022.02.014

Free article

Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

Jet van der Spek et al. Genet Med. 2022 Jun.

Free article

. 2022 Jun;24(6):1283-1296.

doi: 10.1016/j.gim.2022.02.014. Epub 2022 Mar 26.

Authors

Affiliations

¹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
² Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
³ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
⁴ Department of Language and Genetics, 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; Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom.
⁶ Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁷ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Division of Human Genetics, Center for Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University, Semarang, Indonesia.
⁸ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁹ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL.
¹⁰ Department of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
¹¹ Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
¹² Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
¹³ Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany.
¹⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; 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.
¹⁵ CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada.
¹⁶ University Children's Hospital Belgrade, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
¹⁷ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁸ Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
¹⁹ Department of Neuropediatrics, Jena University Hospital, Jena, Germany.
²⁰ Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia.
²¹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
²² Clinical Institute for Genomic Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia.
²³ Department of Neuropaediatrics, Developmental Neurology, Social Pediatrics, University Children's Hospital, University of Tübingen, Tübingen, Germany.
²⁴ Department of Pediatrics, Naval Medical Center Portsmouth, Portsmouth, VA.
²⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁶ Broad Institute Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA.
²⁷ INSMC Alessandrescu-Rusescu, Regional Center of Medical Genetics Bucharest, Bucharest, Romania.
²⁸ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Genetic Health Queensland, Royal Brisbane and Women's hospital, Herston, Queensland, Australia; School of Medicine, Griffith University, Southport, Queensland, Australia.
²⁹ Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
³⁰ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
³¹ Praxis für Humangenetik-Bremen, Bremen, Germany.
³² HudsonAlpha Institute for Biotechnology, Huntsville, AL.
³³ Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands.
³⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands. Electronic address: Tjitske.Kleefstra@radboudumc.nl.

PMID: 35346573
DOI: 10.1016/j.gim.2022.02.014

Abstract

Purpose: Common 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.

Methods: We 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.

Results: Computational 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.

Conclusion: Our 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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Conflict of interest statement

Conflict of Interest M.L.T. is an employee of HudsonAlpha Institute for Biotechnology. For D.M., the following statements are applicable: “Research disclaimer: The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. Copyright statement: I am a military service member. This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.” All other authors declare no conflicts of interest.

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Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

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Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

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