New Pathogenic Variants Associated with Xeroderma Pigmentosum

In a new study appearing in the Proceedings of the National Academy of Sciences, researchers from Nagasaki University in Japan identify cases of Xeroderma pigmentosum (XP) with previously uncharacterized ERCC4/XPF deep intronic founder mutations. XP is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors due to DNA repair deficiency. Among XP, the complementation group F (XP-F) is a rare form, which the authors say is highly underdiagnosed because the affected gene ERCC4/XPF is essential for fetal development. Most of the previously reported cases of this gene's pathogenic variants were hypomorphs causing relatively mild phenotype. In this study, the researchers report 17 XP-F cases with two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which accounts for nearly 10 percent of all Japanese XP cases. It causes an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation is in intron 8 and induces an alternative polyadenylation. "Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations," the authors write. In all the Japanese XP cases identified, the patients developed early-onset skin cancers, indicating that these variants need critical attention, the authors add.