Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability
Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability
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DOI：
10.1038/mp.2016.109
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发表时间：
2017-11-01
影响因子：
11
通讯作者：
Riazuddin, S.
中科院分区：
文献类型：
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作者：
Riazuddin, S.;Hussain, M.;Riazuddin, S.
智力残疾（ID）是一种临床和遗传异质性疾病，影响1-3%的普通人群。虽然对ID遗传原因的研究最近取得了进展，但导致常染色体隐性ID（ARID）的致病性突变的鉴定已经落后，主要是由于无法获得相当大的家庭。在这里，我们提出了121个大的血缘巴基斯坦ID家庭的外显子组测序的结果。在60个家庭中，我们确定了一个单一的基因，30个影响报告ID基因和30个影响新的候选ID基因的纯合或复合杂合DNA变异。这些等位基因的潜在致病性得到了表型共分离、对照群体中频率较低以及严格生物信息学分析的应用的支持。在另外8个家系中观察到多种致病性变异的分离，正常人脑组织的转录组图谱显示，新的候选ID基因形成了一个显著富集的转录共表达网络（P < 0.0001）在胎儿发育期间的额叶皮层和在婴儿期至成年期的颞顶叶和皮质下。此外，12个新的ID基因编码的蛋白质直接与先前报道的ID蛋白质在六个已知的认知功能所必需的途径中相互作用（P < 0.0001）。这些结果表明，中断颞顶叶和皮质下神经发生在婴儿期是至关重要的病理生理学的ID。这些研究结果进一步扩大了现有的剧目的基因参与ARID，并提供了新的见解的分子机制和转录组图谱的ID。
Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P < 0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P < 0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.