Lynch综合症（LS）的某些患者表现出极端表型，即在推荐的筛查年龄之前患上癌症，或者患有没有筛查指南的癌症。我们假设癌症易感性基因（CSG）中的额外种系变异可能解释其中一些表型。我们比较了EO组（30岁之前诊断癌症的患者）和UO组（40岁之后诊断癌症的患者）LS患者中额外CSG变异的患病率。虽然总体上没有差异，但是当只考虑肠道CSG时，我们发现EO病例中致病变异和意义未明变异超量（OR 2.25; 95% CI: 1.01-5.06, p value=0.04）。四个EO病例突出表现出：有两个在关键外切酶结构域中具有POLE/POLD1变异，一个具有BMPR1A重复和一个具有EPCAM缺失。未来的筛查建议应考虑额外的种系变异，因为它们可能会影响癌症风险。© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.

Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. We made the hypothesis that additional germline variants in cancer susceptibility genes (CSG) could explain some of these phenotypes. We compared the prevalence of additional CSG variants in LS patients with a cancer diagnosis before age 30 (early-onset, EO group) and after 40 (usual-onset, UO group). While there was no overall difference, we did find an excess of pathogenic variants and variants of unknown significance in EO cases when only gastrointestinal CSG were considered (OR 2.25; 95% CI: 1.01-5.06, p value = 0.04). Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion. Additional germline variants should be considered in future screening recommendations, as they might influence cancer risk.© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.