Clinical and genetic characteristics of xeroderma pigmentosum in Nepal

Abstract

Background: Little is known about xeroderma pigmentosum (XP) in Himalayan countries.

Objective: To describe clinical characteristics of XP in Nepal and investigate its genetic bases.

Methods: This study was carried out on all consecutive patients referred for XP to a Nepalese tertiary referral centre in 2014-2015. Clinical data were collected using a standardized questionnaire. DNA was extracted from salivary samples, and next-generation sequencing (NGS) was conducted using a panel covering all 8 known XP genes (classical XP (XP-A to XP-G) and XP variant) and a skin cancer modifier gene, the melanocortin 1 receptor gene (MC1R).

Results: Seventeen patients (median age: 15 years; range: 1-32) were included. Twelve had skin cancers (including a total of 8 squamous cell carcinomas, 60 basal cell carcinomas, ocular carcinomas requiring an orbital exenteration in 3 patients, but no melanoma). Fifteen patients carried the same homozygous non-sense XPC mutation c.1243C>T, p.R415X. A homozygous non-sense XPA mutation (p.W235X) was found in the only patient with a history of early severe sunburn reaction and associated neurological symptoms. Associated genetic alterations included heterozygous missense variants in XPD/ERCC2 gene and the presence of MC1R variant R163Q in 5 and 9 patients, respectively.

Conclusion: Although not previously reported, XP seems frequent in Nepal. Patients often presented with a very severe phenotype after a long history of excessive sun exposure without knowledge of the disease. Fifteen of 17 had the same p.R415X XPC mutation, which seems very specific of XP in Nepal, suggesting a founder effect. NGS analyses frequently revealed associated genetic alterations which could play a modifier role in the clinical expression of the disease.