Population-Based Penetrance of Deleterious Clinical Variants
Population-Based Penetrance of Deleterious Clinical Variants
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DOI：
10.1001/jama.2021.23686
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发表时间：
2022-01-25
影响因子：
120.7
通讯作者：
Do, Ron
中科院分区：
文献类型：
--
作者：
Forrest, Iain S.;Chaudhary, Kumardeep;Do, Ron
重要性基于人群的基因变异相关疾病风险评估为临床决策和风险分层方法提供信息。目的评估已知疾病易感基因中临床变异的基于人群的疾病风险。和参与者这项队列研究包括72 434人，37 780个临床变异，他们从2007年开始在BioMe生物库中登记，截至2020年12月，英国生物库从2006年至2010年，随访至2020年6月。参与者将外显子组和电子健康记录数据联系起来，年龄超过20岁，具有不同的祖先backgrounds.EXPOSURES以前报告为致病性或预测通过生物信息学算法导致蛋白质功能丧失的变体（致病性/功能丧失变体）.主要结果和测量主要结果是与临床变体相关的疾病风险。具有变异等位基因的个体的疾病患病率与结果在72434名研究参与者中，43395人来自英国生物样本库，其中43395人来自英国国家生物样本库（平均[SD]年龄，57 [8.0]岁; 24 065 [55%]女性; 2948 [7%]非欧洲人）和29 039来自BioMe生物样本库（平均[SD]年龄，56 [16]岁; 17 355 [60%]女性; 19 663 [68%]非欧洲人）。在5360个致病/功能丧失变异中，4795个（89%）与RD小于或等于0.05相关。ClinVar中报告的致病性变体的平均转移率为6.9%（95% CI，6.0%-7.8%），良性变体的平均转移率为0.85%（95% CI，0.76%-0.95%）（差异为6.0 [95% CI，5.6-6.4]个百分点），由于大量非转移性变体，两组的中位数均为0%。晚发性疾病的致病性/功能丧失变异体的外显率随年龄改变：70岁或以上个体的平均外显率为10.3%（95% CI，9.0%-11.6%），20岁或以上个体为8.5%（95% CI，7.9%-9.1%）（差异为1.8 [95% CI，9.0%-11.6%]）。0.40-3.3]个百分点）。致病性/功能丧失变体的外显率是异质的，即使在已知的疾病易感基因中，包括BRCAI（平均值[范围]，38% [0%-100%]）。BRCA 2（平均值[范围]，38% [0%-100%]）和PAL 82（平均值[范围]，26% [0%-100%]）。结论和相关性在2个大型生物库队列中，致病性/功能丧失变异的估计检出率是可变的，但通常较低。需要对基于人群的等位基因变异率进行进一步研究，以完善对具有这些变异等位基因的个体的变异解释和临床评价。美国医学会杂志
IMPORTANCE Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches.OBJECTIVE To evaluate the population-based disease risk of clinical variants in known disease predisposition genes.DESIGN, SETTING, AND PARTICIPANTS This cohort study included 72 434 individuals with 37 780 clinical variants who were enrolled in the BioMe Biobank from 2007 onwards with follow-up until December 2020 and the UK Biobank from 2006 to 2010 with follow-up until June 2020. Participants had linked exome and electronic health record data, were older than 20 years, and were of diverse ancestral backgrounds.EXPOSURES Variants previously reported as pathogenic or predicted to cause a loss of protein function by bioinformatic algorithms (pathogenic/loss-of-function variants).MAIN OUTCOMES AND MEASURES The primary outcome was the disease risk associated with clinical variants. The risk difference (RD) between the prevalence of disease in individuals with a variant allele (penetrance) vs in individuals with a normal allele was measured.RESULTS Among 72 434 study participants, 43 395 were from the UK Biobank (mean [SD] age, 57 [8.0] years; 24 065 [55%] women; 2948 [7%] non-European) and 29 039 were from the BioMe Biobank (mean [SD] age, 56 [16] years; 17 355 [60%] women; 19 663 [68%] non-European). Of 5360 pathogenic/loss-of-function variants, 4795 (89%) were associated with an RD less than or equal to 0.05. Mean penetrance was 6.9% (95% CI, 6.0%-7.8%) for pathogenic variants and 0.85% (95% CI, 0.76%-0.95%) for benign variants reported in ClinVar (difference, 6.0 [95% CI, 5.6-6.4] percentage points), with a median of 0% for both groups due to large numbers of nonpenetrant variants. Penetrance of pathogenic/loss-offunction variants for late-onset diseases was modified by age: mean penetrance was 10.3% (95% CI, 9.0%-11.6%) in individuals 70 years or older and 8.5% (95% CI, 7.9%-9.1%) in individuals 20 years or older (difference, 1.8 [95% Cl. 0.40-3.3] percentage points). Penetrance of pathogenic/loss-of-function variants was heterogeneous even in known disease predisposition genes, including BRCAI (mean [range], 38% [0%-100%]). BRCA2 (mean [range], 38% [0%-100%]), and PAL82 (mean [range], 26% [0%-100%]).CONCLUSIONS AND RELEVANCE In 2 large biobank cohorts, the estimated penetrance of pathogenic/loss-of-function variants was variable but generally low. Further research of population-based penetrance is needed to refine variant interpretation and clinical evaluation of individuals with these variant alleles. JAMA.