Deep sequencing reveals 50 novel genes for recessive cognitive disorders
Deep sequencing reveals 50 novel genes for recessive cognitive disorders
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DOI：
10.1038/nature10423
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发表时间：
2011-10-06
期刊：
影响因子：
64.8
通讯作者：
Ropers, H. Hilger
中科院分区：
文献类型：
--
作者：
Najmabadi, Hossein;Hu, Hao;Ropers, H. Hilger
常见疾病往往是复杂的，因为它们是遗传异质性的，许多不同的遗传缺陷引起临床上难以区分的表型。早发型认知障碍或智力残疾是已知的最复杂的疾病之一，也是世界范围内非常重要的卫生保健问题。仅X染色体连锁的智力残疾就已确定了90多种不同的基因缺陷，但对更常见的常染色体形式的智力残疾的研究仍处于起步阶段。为了加快常染色体隐性智力残疾的分子阐明，我们现在已经进行了纯合性定位，外显子富集和下一代测序在136个来自伊朗和其他地方的常染色体隐性智力残疾的近亲家庭。这项研究是迄今为止发表的最大的研究，揭示了先前与智力残疾或相关神经系统疾病有关的23个基因中的额外突变，以及50个新候选基因中可能致病的单一变异。这些基因编码的蛋白质直接与已知的智力残疾基因的产物相互作用，许多蛋白质参与基本的细胞过程，如转录和翻译，细胞周期控制，能量代谢和脂肪酸合成，这似乎是正常大脑发育和功能的关键。
Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.