Pilarowski, Genay O.; Vernon, Hilary J.; Applegate, Carolyn D.; Boukas, Leandros; Cho, Megan T.; Gurnett, Christina A.; Benke, Paul J.; Beaver, Erin; Heeley, Jennifer M.; Medne, Livija; Krantz, Ian D.; Azage, Meron; Niyazov, Dmitriy; Henderson, Lindsay B.; Wentzensen, Ingrid M.; Baskin, Berivan; Sacoto, Maria J. Guillen; Bowman, Gregory D.; Bjornsson, Hans T.
Abstract
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.
