High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.

高级别浆液性卵巢癌（HGSOC）具有显着的遗传成分，其中大约一半无法用已知基因解释。为了发现基因，我们分析了 516 名BRCA1/2阴性 HGSOC 女性的种系外显子组测序数据，重点关注富含罕见蛋白质编码功能丧失 (LoF) 变异的基因。总体而言，这些病例中稀有蛋白质编码 LoF 变体显着富集（ p < 0.0001，卡方检验）。只有三十四 (6.6%) 的已知或提议的易感基因具有致病性变异。很少有基因在四个以上的个体中出现 LoF 突变，并且大多数仅在一个个体中检测到。四十三个高排名基因被鉴定为具有三个或更多 LoF 变体，与 GnomAD 相比，这些变体富集了三倍或更多。这些基因代表了不同的功能途径，参与 DNA 修复的基因相对较少，这表明剩余的遗传力大部分是由之前未充分探索的基因和途径来解释的。