J Med Genet 2018 08 2;55(8):561-566. Epub 2017 Sep 2.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
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 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism.
Objectives: To explore whether variants in are associated with a human phenotype.
Methods: We used GeneMatcher to identify other physicians caring for patients with variants in . We also explored the epigenetic consequences of one of these variants in cultured fibroblasts.
Results: Here we describe six 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 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 .
Conclusions: Our results suggest that variants in 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.