Kerr Shona M, Klaric Lucija, Muckian Marisa D, Johnston Kiera, Drake Camilla, Halachev Mihail, Cowan Emma, Snadden Lesley, Dean John, Zheng Sean L, Thami Prisca K, Ware James S, Tzoneva Gannie, Shuldiner Alan R, Miedzybrodzka Zosia, Wilson James F
MRC Human Genetics Unit, University of Edinburgh, Institute of Genetics and Cancer, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
Am J Hum Genet. 2025 Apr 3;112(4):793-807. doi: 10.1016/j.ajhg.2025.02.018. Epub 2025 Mar 14.
The benefits of returning clinically actionable genetic results to participants in research cohorts are accruing, yet such a genome-first approach is challenging. Here, we describe the implementation of return of such results in two founder populations from Scotland. Between 2005 and 2015, we recruited >4,000 adults with grandparents from Orkney and Shetland into the Viking Genes research cohort. The return of genetic data was not offered at baseline, but in 2023, we sent invitations to participants for consent to return of actionable genetic findings. We generated exome sequence data from 4,198 participants and used the American College of Medical Genetics and Genomics (ACMG) v.3.2 list of 81 genes, ClinVar review, and pathogenicity status, plus manual curation, to develop a pipeline to identify potentially actionable variants. We identified 104 individuals (2.5%) with 108 actionable genotypes at 39 variants in 23 genes and validated these. Working with the NHS Clinical Genetics service, which provided genetic counseling and clinical verification of the research results, and after expert clinical review, we notified 64 consenting participants (or their next of kin) of their actionable genotypes. Ten actionable variants across seven genes (BRCA1, BRCA2, ATP7B, TTN, KCNH2, MUTYH, and GAA) have risen 50- to >3,000-fold in frequency through genetic drift in ancestral island localities. Viking Genes is one of the first UK research cohorts to return actionable findings, providing an ethical and logistical exemplar of return of results. The genetic structure in the Northern Isles of Scotland with multiple founder effects provides a unique opportunity for a tailored approach to disease prevention through genetic screening.
将具有临床可操作性的基因检测结果反馈给研究队列中的参与者，益处正在显现，但这种以基因组为先的方法颇具挑战性。在此，我们描述了在苏格兰的两个创始人群体中实施此类结果反馈的情况。2005年至2015年期间，我们招募了4000多名祖父母来自奥克尼和设得兰群岛的成年人加入维京基因研究队列。在基线时未提供基因数据反馈，但在2023年，我们向参与者发出邀请，征求他们对反馈可操作基因检测结果的同意。我们从4198名参与者中生成了外显子组序列数据，并使用美国医学遗传学与基因组学学会（ACMG）第3.2版的81个基因列表、ClinVar评估以及致病性状态，再加上人工筛选，开发了一个流程来识别潜在的可操作变异。我们在23个基因的39个变异位点上，识别出104名个体（2.5%）具有108种可操作基因型，并对这些结果进行了验证。我们与提供基因咨询和研究结果临床验证的英国国民医疗服务体系（NHS）临床遗传学服务部门合作，经过专家临床审查后，我们向64名同意的参与者（或其近亲）通报了他们的可操作基因型。通过在祖先岛屿地区的基因漂变，七个基因（BRCA1、BRCA2、ATP7B、TTN、KCNH2、MUTYH和GAA）中的十个可操作变异的频率上升了50倍至3000倍以上。维京基因研究队列是英国首批反馈可操作研究结果的队列之一，为结果反馈提供了一个伦理和后勤方面的范例。苏格兰北部岛屿具有多种奠基者效应的基因结构，为通过基因筛查进行疾病预防的定制方法提供了独特机会。
