Identification of a novel pathogenic XPC:c.2420 + 1 G>C variant in a patient with xeroderma pigmentosum

Abstract

Xeroderma Pigmentosum group C (XP-C) is a rare, inherited autosomal recessive genetic disorder characterized by extreme sensitivity to ultraviolet (UV) radiation, caused by mutations in the XPC gene. Among the eight XP complementation groups, XP-C is the most prevalent worldwide. Here, we present an 8-year-old girl with multiple discrete hyperpigmented and depigmented macules on her face, neck, upper chest, and arms. Her skin abnormalities first appeared around the age of one as dark patches on the face and neck, progressively worsening with sun exposure. The patient was also diagnosed with bilateral blepharoconjunctivitis and severe dry eye syndrome. Histopathological examination revealed hyperkeratinization of stratified squamous epithelium. Moreover, the proband also exhibited increased expression of PCNA, p53, and cleaved-caspase 3. Genetic analysis identified a novel homozygous pathogenic variant in the XPC gene at c.2420 + 1 G>C. We also demonstrated that the mutant can localize to the site of DNA damage, but it is defective in CPD repair. Among all reported intronic XPC variants, the XPC:c.2420 + 1 G>C mutation seems to have a significant impact as it results in a one-base-pair deletion at the splice donor site of exon 13. This leads to a frameshift, triggering nonsense-mediated decay and causing a premature stop codon in exon 14 of the XPC gene. Thus, the patient is advised to undergo regular examinations to monitor the progression of the disease and the development of precancerous lesions.