Open AccessMissense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy
Author(s) -
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,
Jennifer Friedman,
Pascal Joset,
Katharina Steindl,
Anita Rauch,
Irena J J Muffels,
Peter M. van Hasselt,
Florence 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,
Mahdi M. Motazacker,
Frank J. Kaiser,
Andrew T. Timberlake,
Sabine A. Fuchs,
Christel Depienne,
Cyril Mignot
Publication year - 2021
Publication title -
human genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.351
H-Index - 137
eISSN - 1432-1203
pISSN - 0340-6717
DOI - 10.1007/s00439-021-02283-2
Subject(s) - missense mutation , chromodomain , biology , intellectual disability , genetics , frameshift mutation , epilepsy , exome sequencing , global developmental delay , haploinsufficiency , gene , neuroscience , mutation , helicase , rna , phenotype
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.