Helix, San Mateo, CA, USA.
Renown Institute for Health Innovation, Reno, NV, USA.
Genet Med. 2021 Dec;23(12):2300-2308. doi: 10.1038/s41436-021-01293-9. Epub 2021 Aug 13.
To identify conditions that are candidates for population genetic screening based on population prevalence, penetrance of rare variants, and actionability.
We analyzed exome and medical record data from >220,000 participants across two large population health cohorts with different demographics. We performed a gene-based collapsing analysis of rare variants to identify genes significantly associated with disease status.
We identify 74 statistically significant gene-disease associations across 27 genes. Seven of these conditions have a positive predictive value (PPV) of at least 30% in both cohorts. Three are already used in population screening programs (BRCA1, BRCA2, LDLR), and we also identify four new candidates for population screening: GCK with diabetes mellitus, HBB with β-thalassemia minor and intermedia, PKD1 with cystic kidney disease, and MIP with cataracts. Importantly, the associations are actionable in that early genetic screening of each of these conditions is expected to improve outcomes.
We identify seven genetic conditions where rare variation appears appropriate to assess in population screening, four of which are not yet used in screening programs. The addition of GCK, HBB, PKD1, and MIP rare variants into genetic screening programs would reach an additional 0.21% of participants with actionable disease risk, depending on the population.
根据人群患病率、罕见变异的外显率和可操作性，确定适合进行群体遗传筛查的条件。
我们分析了来自两个具有不同人口统计学特征的大型人群健康队列中超过 220000 名参与者的外显子组和医疗记录数据。我们对罕见变异进行了基于基因的合并分析，以确定与疾病状态显著相关的基因。
我们在 27 个基因中确定了 74 个具有统计学意义的基因-疾病关联。这 7 种情况在两个队列中的阳性预测值（PPV）均至少为 30%。其中三种情况已经在人群筛查计划中使用（BRCA1、BRCA2、LDLR），我们还确定了四个新的人群筛查候选基因：GCK 与糖尿病、HBB 与β-地中海贫血轻微和中间型、PKD1 与囊性肾病以及 MIP 与白内障。重要的是，这些关联是可操作的，因为对这些情况下的每个人进行早期遗传筛查预计将改善结果。
我们确定了七种遗传疾病，其中罕见变异似乎适合在人群筛查中评估，其中四种疾病尚未在筛查计划中使用。将 GCK、HBB、PKD1 和 MIP 罕见变异添加到遗传筛查计划中，将根据人群的不同，使另外 0.21%的具有可操作疾病风险的参与者受益。
