RT Journal Article SR Electronic T1 Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2017-104759 DO 10.1136/jmedgenet-2017-104759 A1 Genay O Pilarowski A1 Hilary J Vernon A1 Carolyn D Applegate A1 Leandros Boukas A1 Megan T Cho A1 Christina A Gurnett A1 Paul J Benke A1 Erin Beaver A1 Jennifer M Heeley A1 Livija Medne A1 Ian D Krantz A1 Meron Azage A1 Dmitriy Niyazov A1 Lindsay B Henderson A1 Ingrid M Wentzensen A1 Berivan Baskin A1 Maria J Guillen Sacoto A1 Gregory D Bowman A1 Hans T Bjornsson YR 2017 UL http://jmg.bmj.com/content/early/2017/09/02/jmedgenet-2017-104759.abstract AB 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.