PT  - JOURNAL ARTICLE
AU  - Genay O Pilarowski
AU  - Hilary J Vernon
AU  - Carolyn D Applegate
AU  - Leandros Boukas
AU  - Megan T Cho
AU  - Christina A Gurnett
AU  - Paul J Benke
AU  - Erin Beaver
AU  - Jennifer M Heeley
AU  - Livija Medne
AU  - Ian D Krantz
AU  - Meron Azage
AU  - Dmitriy Niyazov
AU  - Lindsay B Henderson
AU  - Ingrid M Wentzensen
AU  - Berivan Baskin
AU  - Maria J Guillen Sacoto
AU  - Gregory D Bowman
AU  - Hans T Bjornsson
TI  - Missense variants in the chromatin remodeler <em>CHD1</em> are associated with neurodevelopmental disability
AID  - 10.1136/jmedgenet-2017-104759
DP  - 2017 Sep 02
TA  - Journal of Medical Genetics
PG  - jmedgenet-2017-104759
4099  - http://jmg.bmj.com/content/early/2017/09/02/jmedgenet-2017-104759.short
4100  - http://jmg.bmj.com/content/early/2017/09/02/jmedgenet-2017-104759.full
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.