National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. doi: 10.1016/j.ajhg.2023.08.003. Epub 2023 Aug 30.
Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.
了解作为次要发现 (SFs) 鉴定的致病性变异的外显率对于日益普及的基因检测至关重要。我们通过对接受肥厚型心肌病 (HCM；10400 名受影响个体，1332 种变异) 和扩张型心肌病 (DCM；2564 名受影响个体，663 种变异) 进行诊断测序的个体进行大规模分析，使用横断面方法比较了等位基因频率与参考人群（来自英国生物库和 gnomAD 的 293226 名参与者）。我们生成了 HCM（1:543）和 DCM（1:220）的更新患病率估计值。总体而言，罕见致病性变异（HCM 为 23%，DCM 为 35%）和可能致病性变异（HCM 为 7%，DCM 为 10%）在成年后期的显性心肌病 (CM) 中的外显率相当高。在 HCM 相关基因中，注释为功能丧失或超罕见变体的亚组以及男性变体的外显率明显高于女性变体。我们估计了 316 种最有可能被确定为 SFs 的常见变体的特定变体外显率（在 51%的 HCM 和 17%的 DCM 受影响个体中发现）。在 HCM 相关基因中，观察到 49 个变体至少出现了十次（占受影响个体的 14%）。中位数外显率为 14.6%（±14.4% SD）。我们探讨了按年龄、性别和祖系估计的外显率，并模拟了包括未来队列的影响。该数据集按规模报告了个体变体的外显率，并将为正在接受 SFs 基因筛查的个体的管理提供信息。虽然大多数变体的外显率较低，且筛查的成本和危害尚不清楚，但某些具有高外显率变体的个体可能会从 SFs 中受益。
