It is estimated that 10% of individuals with a myeloid malignancy carry a germline susceptibility. Using the genome-first approach, in which individuals were ascertained on genotype alone, rather than clinical phenotype, we quantified the prevalence and penetrance of pathogenic germline variants in eight myeloid malignancy predisposition (gMMP) genes. ANKRD26, CEBPA, DDX41, MECOM, SRP72, ETV6, RUNX1 and GATA2, were analyzed from the Geisinger MyCode DiscovEHR (n = 170,503) and the United Kingdom Biobank (UKBB, n = 469,595). We identified a high risk of myeloid malignancies (MM) (odds ratio[OR] all genes: DiscovEHR, 4.6 [95% confidential interval (CI) 2.1–9.7], p < 0.0001; UKBB, 6.0 [95% CI 4.3–8.2], p = 3.1 × 10^-27), and decreased overall survival (hazard ratio [HR] DiscovEHR, 1.8 [95% CI 1.3–2.6], p = 0.00049; UKBB, 1.4 [95% CI 1.2–1.8], p = 8.4 × 10^-5) amongst heterozygotes. Pathogenic DDX41 variants were the most commonly identified, and in UKBB showed a significantly increased risk of MM (OR 5.7 [95% CI 3.9–8.3], p = 6.0 × 10^-20) and increased all-cause mortality (HR 1.35 [95% CI 1.1–1.7], p = 0.0063). Through a genome-first approach, this study genetically ascertained individuals with a gMMP and determined their MM risk and survival.

据估计，10% 的髓系恶性肿瘤患者携带种系易感性。使用基因组优先方法，其中仅根据基因型而不是临床表型确定个体，我们量化了 8 个髓系恶性肿瘤易感性 （gMMP） 基因中致病性种系变异的患病率和外显率。ANKRD26、CEBPA、DDX41、MECOM、SRP72、ETV6、RUNX1 和 GATA2 来自 Geisinger MyCode DiscovEHR （n = 170,503） 和英国生物样本库 （UKBB， n = 469,595）。我们确定了髓系恶性肿瘤 （MM） 的高风险 （比值比 [OR] 所有基因：DiscovEHR，4.6 [95% 机密区间 （CI） 2.1-9.7]，p < 0.0001;UKBB，6.0 [95% CI 4.3-8.2]，p = 3.1 × ^10-27），总生存期降低（风险比 [HR] DiscovEHR，1.8 [95% CI 1.3-2.6]，p = 0.00049;杂合子中的 UKBB，1.4 [95% CI 1.2-1.8]，p = 8.4 × ^10-5）。致病性 DDX41 变异是最常见的，在 UKBB 中显示 MM 风险显著增加 （OR 5.7 [95% CI 3.9-8.3]，p = 6.0 × ^10-20）和全因死亡率增加 （HR 1.35 [95% CI 1.1-1.7]，p = 0.0063）。通过基因组优先方法，本研究对患有 gMMP 的个体进行了基因确定，并确定了他们的 MM 风险和生存率。