A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations

Background Xeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumors at an early age. We identified a community in the state of Goias (central Brazil), a very sunny and tropical region, with a high incidence of XP (17 patients among approximately 1,000 inhabitants). Objectives To identify the gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes. Methods Functional analyses of DNA repair capacity and cell cycle responses after ultraviolet exposure were investigated in cells from local XP patients, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community. Results Skin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Polη protein, which is encoded by the POLH gene. We detected two different POLH mutations: one at the splice donor site of intron 6, c.764 +1 G>A, and the other in exon 8, c.907 C>T, p.Arg303X. The mutation at intron 6 is novel, whereas the mutation at exon 8 was previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease. Conclusions and relevance This work describes a genetic cluster involving the POLH gene, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe. This article is protected by copyright. All rights reserved.