Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
Clin Genet. 2019 Jul;96(1):72-84. doi: 10.1111/cge.13554. Epub 2019 May 14.
Variants in the chromodomain helicase DNA-binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate-to-severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non-ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex-dependent penetrance of CHD8 PTVs in humans.
CHD8 基因的变异与智力障碍（ID）、自闭症谱系障碍（ASD）和过度生长有关，CHD8 是 OGID（过度生长和 ID）的致病基因之一。我们研究了 25 名 CHD8 蛋白截断变异（PTV）患者，包括 10 名以前未报道过的患者，发现男性与女性的比例为 2.7:1（19:7），存在共同的特征模式：大头畸形（62.5%）、身材高大（47%）、发育迟缓/智力障碍（81%）、ASD（84%）、睡眠困难（50%）、胃肠道问题（40%）和独特的面部特征。该队列中的大多数个体存在中度至重度 ID，一些个体存在语言退化（37%）、癫痫发作（27%）和低张力（27%），有 2 名个体无法行走。我们的研究表明，CHD8 的杂合性不足与具有明显自闭症特征的明显 OGID 综合征相关，并支持 CHD8 PTV 在人类中存在性依赖的外显率。
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