Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder
Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder
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中国自闭症谱系障碍人群中罕见的拷贝数变异
DOI：
10.3389/fgene.2018.00665
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发表时间：
2018-12-18
影响因子：
3.7
通讯作者：
Yu, Yongguo
中科院分区：
文献类型：
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作者：
Fan, Yanjie;Du, Xiujuan;Yu, Yongguo
自闭症谱系障碍（ASD）在症状和病因上具有异质性。罕见的拷贝数变异（CNVs）是导致ASD的重要遗传因素。目前，染色体微阵列（CMA）检测CNVs被推荐为第一级诊断检测，主要是基于北美和欧洲的研究。罕见的CNV的特征在非欧洲血统的ASD队列中尚未得到很好的表征。在这项研究中，高分辨率CMA被用来研究罕见的CNV在中国ASD队列（n = 401，包括177轻度/中度和224严重影响的个人），以及一个祖先匹配的对照队列（n = 197）。诊断率约为4.2%，在ASD个体中发现了17个具有临床意义的CNV，其中12个CNV与复发性自闭症风险基因座或基因重叠。常染色体罕见CNV负荷分析显示ASD队列中罕见丢失事件的过度表达，而罕见获得事件的发生率与表型严重程度相关。进一步的分析显示，ASD组群中富集了对功能缺失变体高度不耐受的罕见缺失破坏基因。在这些被罕见损失破坏的高度限制基因中，RIMS 2是一个有希望的候选基因，有助于ASD风险。本初步研究评估了CMA的临床应用和中国ASD中罕见CNVs的特征，并确定候选基因为潜在的危险因素。
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 (n = 401, including 177 mildly/moderately and 224 severely affected individuals), together with an ancestry-matched control cohort (n = 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 over-representation 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, RIMS2 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.