Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
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DOI：
10.1016/j.ajhg.2016.12.003
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发表时间：
2017-01-05
影响因子：
9.8
通讯作者：
Raymond, F. Lucy
中科院分区：
文献类型：
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作者：
Carss, Keren J.;Arno, Gavin;Raymond, F. Lucy
遗传性视网膜疾病是视力障碍的常见原因，代表一组高度异质性的疾病。在此，我们展示了 722 名遗传性视网膜疾病患者的研究结果，作为 NIHR-BioResource 罕见疾病研究的一部分，这些患者接受了全基因组测序 (n = 605)、全外显子组测序 (n = 72) 或两者都进行了测序 (n = 45)。我们鉴定了 404/722 (56%) 个体的致病性变异（单核苷酸变异、插入缺失或结构变异）。全基因组测序提供了前所未有的能力来检测三类致病变异，特别是：结构变异、富含GC区域的变异（与全外显子组测序相比，其覆盖范围显着提高）以及非编码调控区域的变异。除了先前报道的致病性调控变异之外，我们还在两名患有无脉络膜血症的男性中鉴定出一种先前未报道的 CHM 致病性内含子变异。我们还鉴定了 19 个以前未知的与遗传性视网膜疾病相关的基因，这些基因在未解决的病例中含有双等位基因预测的蛋白质截短变体。全基因组测序是一种日益重要的综合方法，用于研究遗传性视网膜疾病的遗传原因。
Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.