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Nature:与自闭症相关的遗传因素分析

标签:自闭症 基因
摘要 : Silvia De Rubeis 等人分析了来自3,871个自闭症病例和9,937个祖先相匹配的对照组或亲代对照组的DNA样本,识别出有可能影响患该疾病风险的超过100个常染色体基因。

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泛自闭症(ASD)是一大类脑发育疾病,包括自闭症、儿童期崩解症和阿斯伯格综合症,其特征是社会交往和沟通能力降低、行为反复和兴趣有限。

在本期Nature上发表文章的两个小组采用大规模全外显子组测序方法研究了遗传新生突变和生殖系新生突变对ASD风险的贡献。Silvia De Rubeis 等人分析了来自3,871个自闭症病例和9,937个祖先相匹配的对照组或亲代对照组的DNA样本,识别出有可能影响患该疾病风险的超过100个常染色体基因。新生功能丧失突变在超过5%的自闭症患者身上被检出。相关的基因产物中很多都似乎在突触、转录和染色质重塑通道中发挥功能。

Ivan Iossifov等人对来自超过2,500个家庭(其中每个都有一个患ASD的孩子)的外显子组进行了测序。他们识别出27个高置信度的基因目标,并且估计13%的新生错义突变和43%的“可能会破坏基因的”(LGD)新生突变分别造成所诊断出病例中的12%和9%。

原文摘要:

The contribution of de novo coding mutations to autism spectrum disorder

Ivan Iossifov, Brian J. O’Roak, Stephan J. Sanders, Michael Ronemus, Niklas Krumm, Dan Levy, Holly A. Stessman, Kali T. Witherspoon, Laura Vives, Karynne E. Patterson, Joshua D. Smith, Bryan Paeper, Deborah A. Nickerson, Jeanselle Dea, Shan Dong, Luis E. Gonzalez, Jeffrey D. Mandell, Shrikant M. Mane, Michael T. Murtha, Catherine A. Sullivan,Michael F. Walker, Zainulabedin Waqar, Liping Wei, A. Jeremy Willsey, Boris Yamrom

Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.(doi: 10.1038/nature13772 & doi:10.1038/nature13908

对应Nature杂志: 2014年11月13日Nature杂志精选

来源: Nature 浏览次数:104

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