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

Jet van der Spek, Joery den Hoed, Lot Snijders Blok, Alexander J.M. Dingemans, Dick Schijven, Christoffer Nellaker, Hanka Venselaar, Galuh D.N. Astuti, Tahsin Stefan Barakat, E. Martina Bebin, Stefanie Beck-Wödl, Gea Beunders, Natasha J. Brown, Theresa Brunet, Han G. Brunner, Philippe M. Campeau, Goran Čuturilo, Christian Gilissen, Tobias B. Haack, Irina HüningRalf A. Husain, Benjamin Kamien, Sze Chern Lim, Luca Lovrecic, Janine Magg, Ales Maver, Valancy Miranda, Danielle C. Monteil, Charlotte W. Ockeloen, Lynn S. Pais, Vasilica Plaiasu, Laura Raiti, Christopher Richmond, Angelika Rieß, Eva M.C. Schwaibold, Marleen E.H. Simon, Stephanie Spranger, Tiong Yang Tan, Michelle L. Thompson, Bert B.A. de Vries, Ella J. Wilkins, Marjolein H. Willemsen, Clyde Francks, Lisenka E.L.M. Vissers, Simon E. Fisher, Tjitske Kleefstra*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1283-1296
Number of pages14
JournalGenetics in Medicine
Volume24
Issue number6
DOIs
Publication statusPublished - 1 Jun 2022

Bibliographical note

Funding Information:
We are extremely grateful to all families participating in this study. In addition, we wish to thank the members of the Cell culture facility, Department of Human Genetics, Radboud University Medical Center, Nijmegen for culture of cell lines. This work was financially supported by the Dutch Research Council grant to T.K. (015.014.036 and 1160.18.320) and L.E.L.M.V. (015014066), the Netherlands Organisation for Health Research and Development to T.K. (91718310) and L.E.L.M.V. (843002608, 846002003), by Donders Junior Researcher Grant 2019 to T.K. and L.E.L.M.V. and the Max Planck Society to J.d.H. D.S. C.F. S.E.F. Authors of this publication are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516). The aims of this study contribute to the Solve-RD project (C.G. H.G.B. L.E.L.M.V. and T.K.), which has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement number 779257. For families 10, 13, 14, and 20, sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. For family 16, exome sequencing was performed in the framework of the German project “TRANSLATE NAMSE,” an initiative from the National Action League for People with Rare Diseases (Nationales Aktionsbündnis für Menschen mit Seltenen Erkrankungen, NAMSE), facilitating genetic diagnostics for individuals with suggested rare diseases. Part of this research has been conducted using the UK Biobank Resource under application number 16066, with C.F. as the principal applicant. Our study made use of imaging-derived phenotypes generated by an image-processing pipeline developed by and run on behalf of UK Biobank. Conceptualization: J.v.d.S. J.d.H. L.S.B. C.G. H.G.B. T.K.; Formal Analysis: J.v.d.S. J.d.H. A.J.M.D. D.S.; Investigation: J.v.d.S. J.d.H.; Methodology: J.v.d.S. J.d.H. L.S.B.; Resources: T.S.B. E.M.B. S.B.-W. G.B. N.J.B. T.B. P.M.C. G.C. T.B.H. I.H. R.A.H. B.K. S.C.L. L.L. J.M. A.M. V.M. D.C.M. C.W.O. L.S.P. V.P. L.R. C.R. A.R. E.M.C.S. M.E.H.S. S.S. T.Y.T, M.L.T, E.J.W. M.H.W.; Software: A.J.M.D. D.S. C.N. H.V. G.D.N.A.; Supervision: T.K. S.E.F. L.E.L.M.V. B.B.A.d.V.; Visualization: J.v.d.S. J.d.H.; Writing-Original Draft: J.v.d.S. J.d.H.; Writing-Review and Editing: T.K. S.E.F. L.E.L.M.V. C.F. All study proceedings involving humans were in compliance with the principles set out in the Declaration of Helsinki. This study was approved by the Institutional Review Board “Commissie Mensgebonden Onderzoek Regio Arnhem-Nijmegen” under number 2011/188. Written informed consent for the use and publication of medical data and biological material was obtained from all individuals or their legal representative by the involved clinician. Written informed consent for publication of photographs was obtained specifically and separately. This study includes data from the UK Biobank Study (http://www.ukbiobank.ac.uk).30 UK Biobank received ethical approval from the NHS National Research Ethics Service North West (11/NW/0382) and had obtained informed consent from all participants. The current analyses were conducted under UK Biobank data application number 16066.

Funding Information:
We are extremely grateful to all families participating in this study. In addition, we wish to thank the members of the Cell culture facility, Department of Human Genetics, Radboud University Medical Center, Nijmegen for culture of cell lines. This work was financially supported by the Dutch Research Council grant to T.K. (015.014.036 and 1160.18.320) and L.E.L.M.V. (015014066), the Netherlands Organisation for Health Research and Development to T.K. (91718310) and L.E.L.M.V. (843002608, 846002003), by Donders Junior Researcher Grant 2019 to T.K. and L.E.L.M.V., and the Max Planck Society to J.d.H., D.S., C.F., S.E.F.. Authors of this publication are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516). The aims of this study contribute to the Solve-RD project (C.G., H.G.B., L.E.L.M.V., and T.K.), which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. For families 10, 13, 14, and 20, sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141 . For family 16, exome sequencing was performed in the framework of the German project “TRANSLATE NAMSE,” an initiative from the National Action League for People with Rare Diseases (Nationales Aktionsbündnis für Menschen mit Seltenen Erkrankungen, NAMSE), facilitating genetic diagnostics for individuals with suggested rare diseases. Part of this research has been conducted using the UK Biobank Resource under application number 16066, with C.F. as the principal applicant. Our study made use of imaging-derived phenotypes generated by an image-processing pipeline developed by and run on behalf of UK Biobank.

Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics

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