Carss Keren J, Arno Gavin, Erwood Marie, Stephens Jonathan, Sanchis-Juan Alba, Hull Sarah, Megy Karyn, Grozeva Detelina, Dewhurst Eleanor, Malka Samantha, Plagnol Vincent, Penkett Christopher, Stirrups Kathleen, Rizzo Roberta, Wright Genevieve, Josifova Dragana, Bitner-Glindzicz Maria, Scott Richard H, Clement Emma, Allen Louise, Armstrong Ruth, Brady Angela F, Carmichael Jenny, Chitre Manali, Henderson Robert H H, Hurst Jane, MacLaren Robert E, Murphy Elaine, Paterson Joan, Rosser Elisabeth, Thompson Dorothy A, Wakeling Emma, Ouwehand Willem H, Michaelides Michel, Moore Anthony T, Webster Andrew R, Raymond F Lucy
Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.
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.
遗传性视网膜疾病是视力损害的常见原因，代表了一组高度异质性的病症。在此，我们展示了来自722名遗传性视网膜疾病患者队列的研究结果，这些患者作为英国国家卫生研究院生物资源罕见病研究项目的一部分，进行了全基因组测序（n = 605）、全外显子组测序（n = 72）或两者皆做（n = 45）。我们为404/722（56%）的个体鉴定出了致病变异（单核苷酸变异、插入缺失或结构变异）。全基因组测序尤其赋予了检测三类致病变异前所未有的能力：结构变异、富含GC区域的变异（与全外显子组测序相比，其覆盖度显著提高）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外，我们在两名患有无脉络膜症的男性中，在CHM基因中鉴定出了一个先前未报道的致病性内含子变异。我们还鉴定出了19个先前未知与遗传性视网膜疾病相关的基因，这些基因在未解决病例中含有双等位基因预测的蛋白质截短变异。全基因组测序是一种越来越重要的综合方法，用于研究遗传性视网膜疾病的遗传病因。
