Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Nat Biotechnol. 2016 May;34(5):531-8. doi: 10.1038/nbt.3514. Epub 2016 Apr 11.
Genetic studies of human disease have traditionally focused on the detection of disease-causing mutations in afflicted individuals. Here we describe a complementary approach that seeks to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders. A comprehensive screen of 874 genes in 589,306 genomes led to the identification of 13 adults harboring mutations for 8 severe Mendelian conditions, with no reported clinical manifestation of the indicated disease. Our findings demonstrate the promise of broadening genetic studies to systematically search for well individuals who are buffering the effects of rare, highly penetrant, deleterious mutations. They also indicate that incomplete penetrance for Mendelian diseases is likely more common than previously believed. The identification of resilient individuals may provide a first step toward uncovering protective genetic variants that could help elucidate the mechanisms of Mendelian diseases and new therapeutic strategies.
人类疾病的遗传研究传统上侧重于检测患病个体中的致病突变。在这里，我们描述了一种互补的方法，旨在识别对高度外显遗传形式的儿童期遗传疾病具有弹性的健康个体。对 589306 个人类基因组中的 874 个基因进行全面筛查，发现了 13 名成年人携带有 8 种严重孟德尔疾病的突变，但没有报告表明他们有所述疾病的临床表现。我们的研究结果表明，拓宽遗传研究的范围，系统地寻找缓冲罕见、高度外显、有害突变影响的健康个体是有希望的。它们还表明，孟德尔疾病的不完全外显率可能比以前认为的更为常见。识别具有弹性的个体可能是揭示保护性遗传变异的第一步，这可能有助于阐明孟德尔疾病的机制和新的治疗策略。
