Missense variants in the chromatin remodeler CHD1are associated with neurodevelopmental disability

BackgroundThe list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism.ObjectivesTo explore whether variants in CHD1are associated with a human phenotype.MethodsWe 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.ResultsHere we describe six CHD1heterozygous 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 CHD1gene 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.ConclusionsOur results suggest that variants in CHD1can 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.