Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
J Med Genet
; 55(8): 561-566, 2018 08.
Article
in En
| MEDLINE
| ID: mdl-28866611
BACKGROUND: The list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism. OBJECTIVES: To explore whether variants in CHD1 are associated with a human phenotype. METHODS: We used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts. RESULTS: Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1. CONCLUSIONS: Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Developmental Disabilities
/
DNA Helicases
/
Genetic Predisposition to Disease
/
Mutation, Missense
/
Chromatin Assembly and Disassembly
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DNA-Binding Proteins
/
Genetic Association Studies
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Child
/
Child, preschool
/
Female
/
Humans
/
Infant
Language:
En
Journal:
J Med Genet
Year:
2018
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Reino Unido