Fan Yanjie, Du Xiujuan, Liu Xin, Wang Lili, Li Fei, Yu Yongguo
Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Developmental and Behavioral Pediatrics, Department of Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research & MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Genet. 2018 Dec 18;9:665. doi: 10.3389/fgene.2018.00665. eCollection 2018.
Autism spectrum disorder (ASD) is heterogeneous in symptom and etiology. Rare copy number variations (CNVs) are important genetic factors contributing to ASD. Currently chromosomal microarray (CMA) detecting CNVs is recommended as a first-tier diagnostic assay, largely based on research in North America and Europe. The feature of rare CNVs has not been well characterized in ASD cohorts from non-European ancestry. In this study, high resolution CMA was utilized to investigate rare CNVs in a Chinese cohort of ASD ( = 401, including 177 mildly/moderately and 224 severely affected individuals), together with an ancestry-matched control cohort ( = 197). Diagnostic yield was about 4.2%, with 17 clinically significant CNVs identified in ASD individuals, of which 12 CNVs overlapped with recurrent autism risk loci or genes. Autosomal rare CNV burden analysis showed an overrepresentation of rare loss events in ASD cohort, whereas the rate of rare gain events correlated with the phenotypic severity. Further analysis showed rare losses disrupting genes highly intolerant of loss-of-function variants were enriched in the ASD cohort. Among these highly constrained genes disrupted by rare losses, is a promising candidate contributing to ASD risk. This pilot study evaluated clinical utility of CMA and the feature of rare CNVs in Chinese ASD, with candidate genes identified as potential risk factors.
自闭症谱系障碍（ASD）在症状和病因方面具有异质性。罕见拷贝数变异（CNV）是导致ASD的重要遗传因素。目前，检测CNV的染色体微阵列（CMA）被推荐作为一线诊断检测方法，这主要基于北美和欧洲的研究。在非欧洲血统的ASD队列中，罕见CNV的特征尚未得到很好的描述。在本研究中，利用高分辨率CMA对一个中国ASD队列（n = 401，包括177名轻度/中度和224名重度受影响个体）以及一个与血统匹配的对照队列（n = 197）中的罕见CNV进行了研究。诊断率约为4.2%，在ASD个体中鉴定出17个具有临床意义的CNV，其中12个CNV与复发性自闭症风险位点或基因重叠。常染色体罕见CNV负担分析显示，ASD队列中罕见缺失事件的比例过高，而罕见获得事件的发生率与表型严重程度相关。进一步分析表明，破坏对功能丧失变异高度不耐受基因的罕见缺失在ASD队列中富集。在这些因罕见缺失而破坏的高度受限基因中，[具体基因名称未给出]是导致ASD风险的一个有希望的候选基因。这项初步研究评估了CMA在中国ASD中的临床应用价值以及罕见CNV的特征，并鉴定出候选基因作为潜在风险因素。
