Brigham and Women's Hospital, Division of Genetics Boston, Massachusetts, USA.
Hum Mutat. 2013 Sep;34(9):1216-20. doi: 10.1002/humu.22375. Epub 2013 Aug 5.
It is now affordable to order clinically interpreted whole-genome sequence reports from clinical laboratories. One major component of these reports is derived from the knowledge base of previously identified pathogenic variants, including research articles, locus-specific, and other databases. While over 150,000 such pathogenic variants have been identified, many of these were originally discovered in small cohort studies of affected individuals, so their applicability to asymptomatic populations is unclear. We analyzed the prevalence of a large set of pathogenic variants from the medical and scientific literature in a large set of asymptomatic individuals (N = 1,092) and found 8.5% of these pathogenic variants in at least one individual. In the average individual in the 1000 Genomes Project, previously identified pathogenic variants occur on average 294 times (σ = 25.5) in homozygous form and 942 times (σ = 68.2) in heterozygous form. We also find that many of these pathogenic variants are frequently occurring: there are 3,744 variants with minor allele frequency (MAF) ≥ 0.01 (4.6%) and 2,837 variants with MAF ≥ 0.05 (3.5%). This indicates that many of these variants may be erroneous findings or have lower penetrance than previously expected.
现在，从临床实验室订购经过临床解读的全基因组序列报告已经变得负担得起。这些报告的一个主要组成部分来自先前确定的致病性变异知识库，包括研究文章、特定基因座和其他数据库。虽然已经确定了超过 150,000 个这样的致病性变异，但其中许多最初是在受影响个体的小队列研究中发现的，因此它们对无症状人群的适用性尚不清楚。我们分析了大量无症状个体（N=1092）的大量来自医学和科学文献中的致病性变异的流行率，并在至少一个个体中发现了 8.5%的这些致病性变异。在 1000 基因组计划中的平均个体中，先前确定的致病性变异在纯合形式下平均出现 294 次（σ=25.5），在杂合形式下平均出现 942 次（σ=68.2）。我们还发现，其中许多致病性变异是高频发生的：有 3744 个变异的次要等位基因频率（MAF）≥0.01（4.6%），有 2837 个变异的 MAF≥0.05（3.5%）。这表明，其中许多变异可能是错误的发现，或者比以前预期的穿透率更低。
