Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy.
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Jul 2021
Jul 2021
Historique:
received:
29
01
2021
accepted:
15
04
2021
pubmed:
5
5
2021
medline:
22
6
2021
entrez:
4
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33944996
doi: 10.1007/s00439-021-02283-2
pii: 10.1007/s00439-021-02283-2
pmc: PMC8197709
doi:
Substances chimiques
Nerve Tissue Proteins
0
DNA Helicases
EC 3.6.4.-
CHD5 protein, human
EC 3.6.4.12
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1109-1120Subventions
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP20ek0109348
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP20dm0107090
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP20ek0109486
Organisme : Intramural research grants for Neurological and Psychiatric Disorders of NCNP from the Ministry of Health, Labour and Welfare
ID : 30-6 and 30-7
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP20ek0109301
Organisme : JSPS KAKENHI
ID : JP17H01539
Organisme : JSPS KAKENHI
ID : JP20K08164
Organisme : NHGRI NIH HHS
ID : U01 HG007672
Pays : United States
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP20kk0205012
Organisme : NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director
ID : U01HG007672
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