Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Ilaria Parenti, Daphné Lehalle, Caroline Nava, Erin Torti, Elsa Leitão, Richard Person, Takeshi Mizuguchi, Naomichi Matsumoto, Mitsuhiro Kato, Kazuyuki Nakamura, Stella A. de Man, Heidi Cope, Vandana Shashi, Undiagnosed Diseases Network, Jennifer Friedman, Pascal Joset, Katharina Steindl, Anita Rauch, Irena Muffels, Peter M. van HasseltFlorence Petit, Thomas Smol, Gwenaël Le Guyader, Frédéric Bilan, Arthur Sorlin, Antonio Vitobello, Christophe Philippe, Ingrid M.B.H. van de Laar, Marjon A. van Slegtenhorst, Philippe M. Campeau, Ping Yee Billie Au, Mitsuko Nakashima, Hirotomo Saitsu, Tatsuya Yamamoto, Yumiko Nomura, Raymond J. Louie, Michael J. Lyons, Amy Dobson, Astrid S. Plomp, M. Mahdi Motazacker, Frank J. Kaiser, Andrew T. Timberlake, Sabine A. Fuchs, Christel Depienne*, Cyril Mignot*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)

Abstract

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

Original languageEnglish
Pages (from-to)1109-1120
Number of pages12
JournalHuman Genetics
Volume140
Issue number7
DOIs
Publication statusPublished - 4 May 2021

Bibliographical note

Funding Information:
We thank the patients and their family for their participation in this study. The research generating these results was financially supported by Fondation Maladies Rares, Bio-Psy Labex, “Investissements d’avenir” program ANR-10-IAIHU-06 (IHU-A-ICM), the Japan Agency for Medical Research and Development (AMED) (JP20ek0109486, JP20dm0107090, JP20ek0109301, JP20ek0109348, and JP20kk0205012 to N. M.); JSPS KAKENHI (JP17H01539 to N. M. and JP20K08164 to T. M.); Intramural research grants for Neurological and Psychiatric Disorders of NCNP from the Ministry of Health, Labour and Welfare (30-6 and 30-7 to N. M.), the Takeda Science Foundation (to T. M. and N. M.) and the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number U01HG007672 (Duke University). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
Open Access funding enabled and organized by Projekt DEAL. The research generating these results was financially supported by Fondation Maladies Rares, Bio-Psy Labex, “Investissements d’avenir” program ANR-10-IAIHU-06 (IHU-A-ICM), the Japan Agency for Medical Research and Development (AMED) (JP20ek0109486, JP20dm0107090, JP20ek0109301, JP20ek0109348, and JP20kk0205012 to N. M.); JSPS KAKENHI (JP17H01539 to N. M. and JP20K08164 to T. M.); Intramural research grants for Neurological and Psychiatric Disorders of NCNP from the Ministry of Health, Labour and Welfare (30-6 and 30-7 to N. M.), the Takeda Science Foundation (to T. M. and N. M.), and the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number U01HG007672 (Duke University).

Publisher Copyright:
© 2021, The Author(s).

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