Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Dr. Li Dak-Sum Research Centre, The University of Hong Kong-Karolinska Institutet Collaboration in Regenerative Medicine, Hong Kong, China.
Hum Genet. 2018 Jan;137(1):31-37. doi: 10.1007/s00439-017-1852-1. Epub 2017 Nov 11.
Recently, the American College of Medical Genetics (ACMG) recommended the return of actionable secondary findings detected from clinical sequencing. The reported frequency of secondary findings in Asian populations were highly variable and it is unclear whether the uniformity in coverage offered by whole-genome sequencing (WGS) may impact the estimate. In this analysis, we aimed to refine the rate of secondary findings on East Asians through a large-scale WGS study. We classified 1256 protein-altering or splicing variants of the 59 actionable genes detected from WGS of 954 East Asians in strict accordance with the ACMG and the Association for Molecular Pathology guidelines. A total of 21 pathogenic or likely pathogenic variants were detected in 24 of the 954 East Asian genomes with an estimate of 2.5% of East Asians carrying actionable variants. Although the overall estimate of secondary findings was consistent with those reported for non-East Asian ethnicities, genetic and allelic heterogeneity was observed. WGS offers a wider breadth of coverage over WES, which highlights the need to further investigate the variable sensitivity of WES and WGS in the detection of secondary findings. Identifying secondary findings in populations underrepresented in previous genetic literature might improve variant interpretation and has a profound impact on local decision-making with regard to the cost-effectiveness of returning the secondary findings from clinical sequencing.
最近，美国医学遗传学学院（ACMG）建议将从临床测序中检测到的可操作的次要发现返还给患者。亚洲人群中报告的次要发现频率差异很大，目前尚不清楚全基因组测序（WGS）提供的全覆盖是否会影响这一估计。在这项分析中，我们旨在通过一项大规模的 WGS 研究来细化东亚人群的次要发现率。我们严格按照 ACMG 和分子病理学协会的指南，对从 954 名东亚人 WGS 中检测到的 59 个可操作基因的 1256 个蛋白改变或剪接变异进行分类。在 954 个东亚人基因组中的 24 个基因组中检测到 21 个致病性或可能致病性变异，估计有 2.5%的东亚人携带可操作的变异。虽然次要发现的总体估计与非东亚人群的报告一致，但也观察到了遗传和等位基因异质性。WGS 提供了比 WES 更广泛的覆盖范围，这凸显了需要进一步研究 WES 和 WGS 在检测次要发现时的可变敏感性。在遗传文献中代表性不足的人群中识别次要发现可能会改善变异解释，并对临床测序中返回次要发现的成本效益的本地决策产生深远影响。
