子宫内膜异位症是育龄妇女常见的慢性疾病。病程可能具有高度侵袭性，需要大量手术。子宫内膜异位症的病因仍然难以捉摸，但其高遗传力已得到证实。已经确定了几个低外显率易感位点，但高风险易感性仍未确定。众所周知，子宫内膜异位症会增加上皮性卵巢癌的风险，尤其是子宫内膜样癌和透明细胞类型的癌症。在这里，我们分析了一个芬兰家庭，其中四名女性被诊断患有经手术证实的、症状严重的子宫内膜异位症，其中两名患者还患有高级别浆液性癌。全外显子组测序揭示了三种与子宫内膜异位症分离的罕见候选易感变异。变体是 FGFR4 中的 c.1238C>T, p.(Pro413Leu)、NALCN 中的 c.5065C>T, p.(Arg1689Trp) 和 NAV2 中的 c.2086G>A, p.(Val696Met)。计算机工具预测的唯一有害变体是 FGFR4 中的变体。对 92 名芬兰子宫内膜异位症患者和 19 名子宫内膜异位症-卵巢癌患者的变异体进行进一步筛查，没有发现其他携带者。组织病理学、阳性p53免疫染色和遗传分析支持该家族中两种肿瘤的高级别浆液性亚型。在这里，我们提供FGFR4、NALCN和NAV2作为家族性子宫内膜异位症的新高风险候选基因。我们的结果也支持子宫内膜异位症与高级别浆液性癌的关联。需要进一步的研究来验证这些发现并揭示子宫内膜异位症的确切发病机制。阐明子宫内膜异位症的遗传背景可明确该疾病的病因，并为快速诊断和个性化治疗提供机会。© 2023。BioMed Central Ltd.，Springer Nature 旗下公司。

Endometriosis is a common, chronic disease among fertile-aged women. Disease course may be highly invasive, requiring extensive surgery. The etiology of endometriosis remains elusive, though a high level of heritability is well established. Several low-penetrance predisposing loci have been identified, but high-risk susceptibility remains undetermined. Endometriosis is known to increase the risk of epithelial ovarian cancers, especially of endometrioid and clear cell types. Here, we have analyzed a Finnish family where four women have been diagnosed with surgically verified, severely symptomatic endometriosis and two of the patients also with high-grade serous carcinoma.Whole-exome sequencing revealed three rare candidate predisposing variants segregating with endometriosis. The variants were c.1238C>T, p.(Pro413Leu) in FGFR4, c.5065C>T, p.(Arg1689Trp) in NALCN, and c.2086G>A, p.(Val696Met) in NAV2. The only variant predicted deleterious by in silico tools was the one in FGFR4. Further screening of the variants in 92 Finnish endometriosis and in 19 endometriosis-ovarian cancer patients did not reveal additional carriers. Histopathology, positive p53 immunostaining, and genetic analysis supported the high-grade serous subtype of the two tumors in the family.Here, we provide FGFR4, NALCN, and NAV2 as novel high-risk candidate genes for familial endometriosis. Our results also support the association of endometriosis with high-grade serous carcinoma. Further studies are required to validate the findings and to reveal the exact pathogenesis mechanisms of endometriosis. Elucidating the genetic background of endometriosis defines the etiology of the disease and provides opportunities for expedited diagnostics and personalized treatments.© 2023. BioMed Central Ltd., part of Springer Nature.