Comprehensive germline mutation analysis and clinical profile in a large cohort of Brazilian xeroderma pigmentosum patients
Karina Miranda Santiago, Ligia Pereira Castro, João Pedreira Duprat Neto, Amanda França de Nóbrega, C. A. L. Pinto, Patrícia Ashton‐Prolla, Filippo Pinto e Vairo, Paula Frassinetti Vasconcelos de Medeiros, Erlane Marques Ribeiro, Bethania F.R. Ribeiro, F.F. do Valle, Maria Juliana R. Doriqui, C.H.B. Leite, Rafael Malagoli Rocha, Livia Maria Silva Moura, Veridiana Munford, Pedro A. F. Galante, Carlos Frederico Martins Menck, Sílvia Regina Rogatto, Maria Isabel Achatz
Abstract
BACKGROUND: Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system. OBJECTIVES: To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP. METHODS: Twenty-seven families were screened for germline variants in eight XP-related genes. RESULTS: All patients (N = 32) were diagnosed with bi-allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251-1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2/XPD, DDB2/XPE and ERCC5/XPG variants were found in a few patients. Aside from melanoma and non-melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma. CONCLUSIONS: We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP-related genes, unexpected non-skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described.