Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, 19857 Tehran, Iran.
Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
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.
常见疾病通常较为复杂，因为它们在遗传上具有异质性，许多不同的遗传缺陷导致临床表型无法区分。这在早发性认知障碍或智力障碍中得到了充分证明，智力障碍是已知最复杂的疾病之一，也是全球范围内非常重要的医疗保健问题。仅 X 染色体连锁智力障碍就已确定了 90 多种不同的基因缺陷，但对更常见的常染色体智力障碍形式的研究仍处于起步阶段。为了加速常染色体隐性智力障碍的分子阐明，我们现在对来自伊朗和其他地区的 136 个常染色体隐性智力障碍的近亲家庭进行了纯合子作图、外显子富集和下一代测序。这项迄今为止规模最大的研究揭示了 23 个先前与智力障碍或相关神经发育障碍相关的基因中的额外突变，以及 50 个新候选基因中的单个、可能致病的变异。这些基因编码的蛋白质直接与已知智力障碍基因的产物相互作用，许多基因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，这些过程似乎对正常的大脑发育和功能至关重要。
