The study of Lynch syndrome in a special population reveals a strong founder effect and an unusual mutational mechanism in familial adenomatous polyposis

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 …