1 in 38 individuals at risk of a dominant medically actionable disease
1 in 38 individuals at risk of a dominant medically actionable disease
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DOI：
10.1038/s41431-018-0284-2
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发表时间：
2019-02-01
影响因子：
5.2
通讯作者：
Yntema, Helger G.
中科院分区：
文献类型：
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作者：
Haer-Wigman, Lonneke;van der Schoot, Vyne;Yntema, Helger G.
临床基因组测序可以识别与最初的临床问题无关但与患者及其家人具有医学相关性的致病变异。随着关于披露或搜索此类变异的效用的持续讨论，获得对这些偶然或次要发现的普遍性的公正见解至关重要，以便更好地权衡潜在的风险和收益。之前的研究报告了广泛的次要发现，范围从 1% 到 9%，这仅仅是由于研究设计、测试队列、使用的测序技术和基因分析的差异。在这里，我们分析了 1640 名匿名健康荷兰人的 WES 数据，以确定欧洲血统的近交群体中可医学治疗的疾病等位基因的频率。我们的研究表明，每 38 名健康个体中就有 1 名 (2.7%) 在美国医学遗传学与基因组学学院 (ACMG) 建议披露的 59 种医学上可行的显性疾病基因之一中存在（可能）致病性变异。此外，我们还发现 36 人 (2.2%) 是隐性致病等位基因的携带者。尽管这些次要发现的频率与东亚人群中报道的一致，但致病性变异在 59 个 ACMG 基因中的分布不同。我们的结果有助于关于健康个体遗传风险因素筛查的辩论，以及这种知识和相关预防方案的潜在益处是否超过测试结果的情绪影响和可能的耻辱的风险的讨论。
Clinical genomic sequencing can identify pathogenic variants unrelated to the initial clinical question, but of medical relevance to the patients and their families. With ongoing discussions on the utility of disclosing or searching for such variants, it is of crucial importance to obtain unbiased insight in the prevalence of these incidental or secondary findings, in order to better weigh potential risks and benefits. Previous studies have reported a broad range of secondary findings ranging from 1 to 9%, merely attributable to differences in study design, cohorts tested, sequence technology used and genes analyzed. Here, we analyzed WES data of 1640 anonymized healthy Dutch individuals to establish the frequency of medically actionable disease alleles in an outbred population of European descent. Our study shows that 1 in 38 healthy individuals (2.7%) has a (likely) pathogenic variant in one of 59 medically actionable dominant disease genes for which the American College of Medical Genetics and Genomics (ACMG) recommends disclosure. Additionally, we identified 36 individuals (2.2%) to be a carrier of a recessive pathogenic disease allele. Whereas these frequencies of secondary findings are in line with what has been reported in the East-Asian population, the pathogenic variants are differently distributed across the 59 ACMG genes. Our results contribute to the debate on genetic risk factor screening in healthy individuals and the discussion whether the potential benefits of this knowledge and related preventive options, outweigh the risk of the emotional impact of the test result and possible stigmatization.