Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study
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DOI：
10.1016/s0140-6736(12)61480-9
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发表时间：
2012-11-10
期刊：
影响因子：
168.9
通讯作者：
Strom, Tim M.
中科院分区：
文献类型：
--
作者：
Rauch, Anita;Wieczorek, Dagmar;Strom, Tim M.
背景大多数患者智力残疾的遗传原因尚不清楚，因为缺乏形态线索、关于这些基因位置的信息以及合适的筛查方法。我们的目的是在散发性非综合征性智力残疾患者中识别去新生变异。方法在这项研究中，我们从德国和瑞士的10个中心招募了智力残疾儿童及其父母。我们比较了患者和他们的父母之间的外显子组序列，以识别去新生变体。来自KORA Augsburg糖尿病家庭研究的20名儿童及其父母作为对照进行了调查。结果我们从德国智力低下网络招募了51名参与者。病例组中45人(88%)和对照组中14人(70%)有去新生变异。我们在病例组中发现了87个去新生变异体，每个个体每代的外显子突变率为1.71。在对照组中，我们确定了24个去新生变异体，即每个个体每代1.2次事件。与对照组相比，病例组中有更多的参与者出现功能丧失变异(20/51比2/20；p=0.022)，这表明他们对疾病的发展有贡献。16例患者携带3个重复突变基因(STXBP1、SYNGAP1和SCN2A)的已知智能障碍基因的去新变种。我们认为六个新基因中至少有六个功能丧失突变是疾病的致病因素。我们还发现了几个具有潜在致病作用的错义改变。排除拷贝数变异、去新生点突变和小INDELs后的解释与严重的、散发性的非综合征性智能障碍有关，占高基因座异质性患者的45%-55%。常染色体隐性遗传在被调查的外交群体中的作用似乎很小。已知的智力残疾基因中大量的从头变异只能部分归因于已知的非特定表型。一些患者没有达到预期的症状表现，这表明目前的临床症状描述存在很大的偏见。
Background The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability.Methods In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls.Findings We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1.71 per individual per generation. In the control group we identifi ed 24 de-novo variants, which is 1.2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0.022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identifi ed several missense alterations with potential pathogenicity.Interpretation After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions.