Abstract
Xeroderma pigmentosum (XP) is a rare genetic condition in which exposure to sunlight leads to a high tumor incidence due to defective DNA repair machinery. Herein, we investigated seven patients clinically diagnosed with XP living in a small city, Montanhas (Rio Grande do Norte), in the Northeast region of Brazil. We performed high-throughput sequencing and, surprisingly, identified two different mutated genes. Six patients carry a novel homozygote mutation in the POLH/XPV gene, c.672_673insT (p.Leu225Serfs*33), while one patient carries a homozygote mutation in the XPC gene, c.2251-1G>C. This latter mutation was previously described in Southeastern Africa (Comoro Island and Mozambique), Pakistan, and in a high incidence in Brazil. The XP-C patient had the first symptoms before the first year of life with aggressive ophthalmologic tumor progression and a melanoma onset at 7 years of age. The XP-V patients presented a milder phenotype with later onset of the disorder (mean age of 16 years old), and one of the six XP-V patients developed melanoma at 72 years. The photoprotection is minimal among them, mainly for the XP-V patients. The differences in the disease severity between XP-C (more aggressive) and XP-V (milder) patients are obvious and point to the major role of photoprotection in the XPs. We estimate that the incidence of XP patients at Montanhas can be higher, but with no diagnosis, due to poor health assistance. Patients still suffer from the stigmatization of the condition, impairing diagnosis, education for sun protection, and medical care.
Highlights
Xeroderma pigmentosum is an autosomal recessive disease in which the patients develop a high frequency of skin cancer, internal tumors, and neurological abnormalities (20–30% of the patients) (Menck and Munford, 2014)
We provided the molecular diagnosis for 7 Xeroderma pigmentosum (XP) patients, out of 13, at Montanhas, a small city in the south of Rio Grande do Norte (RN), Brazil
Even in this extreme condition, where the XP patients have lived under a high amount of sunlight exposure, only one XP-V developed melanoma at 73 years of age, which is different from the XP-C patient, who was diagnosed with a melanoma at 7 years of age, indicating that the variation in clinical phenotypes observed in the XP patients might be due to the different mutated genes involved in their prognosis
Summary
Xeroderma pigmentosum is an autosomal recessive disease in which the patients develop a high frequency of skin cancer, internal tumors, and neurological abnormalities (20–30% of the patients) (Menck and Munford, 2014). The transcription-coupled repair (TCR), in which the recognition occurs on the transcribed strand by the arrest of the RNA polymerase, and the nontranscribed genome is repaired by the global genomic repair (GGR) pathway (Hanawalt, 2002) These pathways are responsible for correctly cleaning up the DNA from lesions induced mainly by the ultraviolet radiation (UVR) from sunlight. By performing the next-generation sequencing (NGS) with a specific panel of DNA repair genes, we identified homozygous mutations in two different genes: POLH (six patients) and XPC (one patient). This is the second XP genetic cluster described in Brazil (Munford et al, 2017), but the first to identify two different mutated XP genes in such a small community. The pedigrees were drawn following the Standardized Human Pedigree Nomenclature (Bennett et al, 1995)
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