Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability.

Abstract

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 <i>CHD1</i> have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism. To explore whether variants in <i>CHD1</i> are associated with a human phenotype. We used GeneMatcher to identify other physicians caring for patients with variants in <i>CHD1</i>. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts. Here we describe six <i>CHD1</i> 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 <i>CHD1</i> 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 <i>CHD1</i>. Our results suggest that variants in <i>CHD1</i> 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.