A Splicing Variant in XPA Results in Delayed Onset of Clinical Features of Xeroderma Pigmentosum

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by defective nucleotide excision repair (NER), leading to extreme sensitivity to sunlight-induced skin pigmentation changes and increased skin cancer risk. Patients with XP present with varying severity, often influenced by specific variants in NER-associated genes. In this study, we describe 2 unrelated Cypriot patients with XP-A with a mild phenotype linked to a homozygous missense variant in XPA (ENST00000375128.5:c.389G>A/ENSP00000364270.5:p.R130K, further referred to as XPA^c.389G>A/XPA^R130K). The older patient, aged 69 years, developed progressive neurological degeneration in his 40s, whereas the younger patient, aged 32 years, has no neurological abnormalities to date. Molecular analysis revealed a severe transcription-coupled NER defect and reduced global genome repair (global genome NER) in patient fibroblasts, consistent with the XP-A diagnosis. Surprisingly, very low XPA protein levels were detected, despite the conservative amino acid substitution. Further experiments demonstrated that although the XPA^R130K protein variant is both stable and functional in NER, it is a splice defect in the XPA^c.389G>A gene in patients that leads to reduced XPA mRNA levels, ultimately explaining the low protein levels and residual NER activity in patients. This study highlights the complex relationship between genotype, splicing, and clinical phenotype in patients with XP-A.