We read with interest the study by Moller and colleagues.1 The isolation and relative homogeneity of the Saudi population enhance the potential to discover founder mutations, while its high rates of consanguinity enhances homozygosity even for typically dominant disease genes.2 3 We have previously explored the contribution of Lynch syndrome (LS) to colorectal cancer (CRC) based on ~800 Saudi patients.4 We have since expanded our cohort to 1207 CRC patients. Of the 112 mismatch repair deficient (dMMR) cases, MMR gene mutations were identified in 26 cases and these varied in their cancer risk by age 50 years (figure 1). Three founder mutations were observed, accounting for 42.3% (n=11) of LS cases, and none is listed in gnomAD. The PMS2 :c.1376C>G;p.S459X variant was the most commonly encountered LS variant (n=6), and we calculated its minor allele frequency at 0.0001. ​ Importantly, we were able to identify a homozygous individual for PMS2 :c.1376C>G;p.S459X through a large scale whole-exome sequencing (WES) study.2 This individual presented at age 8 years with haematochezia and a typical picture of familial adenomatous …

中文翻译：

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在特殊人群中对 Lynch 综合征的研究揭示了家族性腺瘤性息肉病的强烈创始人效应和不寻常的突变机制

我们饶有兴趣地阅读了 Moller 及其同事的研究。1 沙特人口的​​隔离性和相对同质性增强了发现创始人突变的可能性，而其高血缘率提高了即使对于典型的显性疾病基因的纯合性。2 3 我们之前已经探索过基于约 800 名沙特患者的 Lynch 综合征 (LS) 对结直肠癌 (CRC) 的贡献。4 此后我们将队列扩大到 1207 名 CRC 患者。在 112 例错配修复缺陷 (dMMR) 病例中，有 26 例发现 MMR 基因突变，并且随着 50 岁年龄的增长，这些病例的癌症风险各不相同（图 1）。观察到三个创始人突变，占 LS 病例的 42.3% (n=11)，并且没有在 gnomAD 中列出。PMS2 :c.1376C>G;p.S459X 变体是最常见的 LS 变体 (n=6)，我们计算出它的次要等位基因频率为 0.0001。重要的是，我们能够通过大规模全外显子组测序 (WES) 研究确定 PMS2 的纯合个体：c.1376C>G;p.S459X。2 该个体在 8 岁时出现便血和典型图片家族性腺瘤性…