TY - JOUR
T1 - Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability
AU - Pilarowski, Genay O.
AU - Vernon, Hilary J.
AU - Applegate, Carolyn D.
AU - Boukas, Leandros
AU - Cho, Megan T.
AU - Gurnett, Christina A.
AU - Benke, Paul J.
AU - Beaver, Erin
AU - Heeley, Jennifer M.
AU - Medne, Livija
AU - Krantz, Ian D.
AU - Azage, Meron
AU - Niyazov, Dmitriy
AU - Henderson, Lindsay B.
AU - Wentzensen, Ingrid M.
AU - Baskin, Berivan
AU - Sacoto, Maria J.Guillen
AU - Bowman, Gregory D.
AU - Bjornsson, Hans Tomas
N1 - Publisher Copyright:
© 2018 Article author(s) (or their employer(s) unless otherwise stated in the text of the article). All rights reserved.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
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.
KW - chromatin
KW - epigenetic machinery
KW - human disease
KW - neurological dysfunction
KW - speech apraxia
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U2 - 10.1136/jmedgenet-2017-104759
DO - 10.1136/jmedgenet-2017-104759
M3 - Article
C2 - 28866611
AN - SCOPUS:85042436222
SN - 0022-2593
VL - 55
SP - 561
EP - 566
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 8
ER -