Different germline variants in the XPA gene are associated with severe, intermediate, or mild neurodegeneration in...

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by pathogenic variants in seven nucleotide excision repair genes (XPA to XPG) and POLH involved in translesion synthesis. XP patients have a >1000-fold increased risk for sunlight-induced skin cancers. Many Japanese XP-A patients have severe neurological symptoms due to a founder variant in intron 3 of the XPA gene. However, in the United States we found XP-A patients with milder clinical features. We developed a simple scoring scale to assess XP-A patients of varying neurological disease severity. We report 18 XP-A patients examined between 1973 and 2023 under an IRB approved natural history study. Using our scale, we classified our XP-A cohort into severe (n = 8), intermediate (n = 5), and mild (n = 5) disease groups at age 10 years. DNA repair tests demonstrated greatest reduction of DNA repair in cells from severe patients as compared to cells from mild patients. Nucleotide sequencing identified 18 germline pathogenic variants in the 273 amino acid, 6 exon-containing XPA gene. Based on patient clinical features, we associated these XPA variants to severe (n = 8), intermediate (n = 6), and mild (n = 4) clinical phenotypes in the patients. Protein structural analysis showed that nonsense and frameshift premature stop codon pathogenic variants located in exons 3 and 5 correlated with severe disease. Intermediate disease correlated with a splice variant at the last base in exon 4. Mild disease correlated with a frameshift variant in exon 1 with a predicted re-initiation in exon 2; a splice variant that created a new strong donor site in intron 4; and a large genomic deletion spanning exon 6. Our findings revealed correlations between disease severity, DNA repair capacity, and XPA variant type and location. In addition, both XPA alleles contributed to the phenotypic differences in XP-A patients.