Novel germline ERCC5 mutations identified in a xeroderma pigmentosum complementation group G pedigree

Xeroderma pigmentosum (XP) is an autosomal recessive genodermatosis caused by a germline loss of function in DNA repair enzymes.1, 2 This defect impairs physiologic DNA repair after ultraviolet (UV) radiation–induced damage, which can lead to photosensitivity in about half of all patients,3, 4 pigmentation abnormalities, and an increased risk of nonmelanoma skin cancers as well as melanoma.5 XP patients classically exhibit a 10,000-fold increase in the frequency of skin cancers arising in sun-exposed skin, eyes, and other mucosal areas (eg, lips and tongue), which appear at an early age.5 Prognosis and mortality of XP patients are mostly tightly related to the risk of metastasis of cutaneous squamous cell carcinomas and melanomas but also depend on the extent of the underlying DNA repair deficiency. The life expectancy of XP patients is reduced by 30 years.2, 6 Seven genetically distinct complementation groups of XP (designated XP-A through XP-G depending on the gene mutated) with germline loss of function mutations to enzymes are involved in nucleotide excision repair (NER).6 The degree of photosensitivity, risk of skin cancer, and risk of neurologic abnormality vary from complementation group to group.3 XP complementation group G (XP-G, OMIM 278780) represents one of the rarest subtypes of XP with mutations identified in the Excision Repair Cross-complementing Rodent Repair Deficiency Complementation Group 5 gene (ERCC5), which encodes an enzyme involved in the incision step during the removal of UV-damaged DNA. XP-G is one of the most clinically lethal subtypes of XP, wherein patients also exhibit clinical features of Cockayne syndrome (CS) or XP with neurologic symptoms. To date, there have been less than 20 XP-G cases reported in the literature.7, 8 Approximately 30 noncutaneous malignancies have also been associated with this lethal XP subtype.9 Herein, we report a Chinese proband patient who had XP group G diagnosed, resulting from 2 compound heterozygous germline mutations in ERCC5—a nonsense mutation from the father and a missense mutation from the mother. To the best of our knowledge, this patient is the first reported XP-G case identified in the Chinese population.