Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability. Issue 8 (2nd September 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of medical genetics. Volume 55:Issue 8(2018)
• Page Start: 561
• Page End: 566
• Publication Date: 2017-09-02
• Subjects: human disease -- neurological dysfunction -- epigenetic machinery -- chromatin -- speech apraxia; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2017-104759
• Languages: English
• ISSNs: 1468-6244

Abstract

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.