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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Parenti, I; Lehalle, D; Nava, C; Torti, E; Leitão, E; Person, R; Mizuguchi, T; Matsumoto, N; Kato, M; Nakamura, K; de Man, SA; Cope, H; Shashi, V; Undiagnosed Diseases Network, ; Friedman, J; Joset, P; Steindl, K; Rauch, A; Muffels, I; van Hasselt, PM; Petit, F; Smol, T; Le Guyader, G; Bilan, F; Sorlin, A; Vitobello, A; Philippe, C; van de Laar, IMBH; van Slegtenhorst, MA; Campeau, PM; Au, PYB; Nakashima, M; Saitsu, H; Yamamoto, T; Nomura, Y; Louie, RJ; Lyons, MJ; Dobson, A; Plomp, AS; Motazacker, MM; Kaiser, FJ; Timberlake, AT; Fuchs, SA; Depienne, C; Mignot, C

Published Date

  • July 2021

Published In

Volume / Issue

  • 140 / 7

Start / End Page

  • 1109 - 1120

PubMed ID

  • 33944996

Pubmed Central ID

  • PMC8197709

Electronic International Standard Serial Number (EISSN)

  • 1432-1203

Digital Object Identifier (DOI)

  • 10.1007/s00439-021-02283-2


  • eng

Conference Location

  • Germany