Clinical and genetic characteristics of xeroderma pigmentosum in Nepal

Summary

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 (XPA to XPG) 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 nonsense XPC mutation c.1243C>T, p.R415X. A homozygous nonsense XPA mutation (p.W235X) was found in the only patient with a history of early severe sunburn reaction and associated neurologic 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. 15/17 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.

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