Correlation of Phenotype/Genotype in a Cohort of 23 Xeroderma Pigmentosum-Variant Patients Reveals 12 New Disease-Causing POLH Mutations

ABSTRACT Xeroderma pigmentosum variant (XP‐V) is a rare genetic disease, characterized by some sunlight sensitivity and predisposition to cutaneous malignancies. We described clinical and genetic features of the largest collection ever published of 23 XP‐V patients (ages between 21 and 86) from 20 unrelated families. Primary fibroblasts from patients showed normal nucleotide excision repair but UV‐hypersensitivity in the presence of caffeine, a signature of the XP‐V syndrome. 87% of patients developed skin tumors with a median age of 21 for the first occurrence. The median numbers of basal‐cell carcinoma was 13 per patient, six for squamous‐cell carcinoma, and five for melanoma. XP‐V is due to defects in the translesion‐synthesis DNA polymerase Polη coded by the POLH gene. DNA sequencing of POLH revealed 29 mutations, where 12 have not been previously identified, leading to truncated polymerases in 69% of patients. Four missense mutations are correlated with the protein stability by structural modeling of the Polη polymerase domain. There is a clear relationship between the types of missense mutations and clinical severity. For truncating mutations, which lead to an absence of or to inactive proteins, the life‐cumulated UV exposure is probably the best predictor of cancer incidence, reinforcing the necessity to protect XP‐Vs from sun exposure. Point mutations located in the active site of the translesion polymerase η dictate the clinical aggressiveness of the xeroderma pigmentosum variant syndrome. The mutated proteins are unable to faithfully replicate through UV‐induced DNA lesions leading, therefore, to numerous skin cancers. This picture represents a replication fork with orange parental template and yellow primer strand. The mutations in the active domain are highlighted (for example R93P: Arg93Pro) in different colors.