Identification Of Variants In POLH Gene Causing Xeroderma Pigmentosum Variant Type In A Consanguineous Chinese Family

Background: Xeroderma pigmentosum(XP)is a rare autosomal recessive genetic disease characterized by increased sensitivity to ultraviolet radiation,freckle-like pigment deposition,and significantly increased risk of skin cancer.It is caused by defects in nucleotide excision repair.The XP variant type known as XPV is caused by mutations in the POLH gene,which encodes DNA polymerase eta(POLη)and plays an important role in translesion synthesis.Loss of POLη function can lead to the use of another TLS polymerase that is more error-prone during replication,resulting in XPV.Objective: To perform whole-exome sequencing and Sanger sequencing on a Chinese family with XP to identify POLH gene mutations and predict the structure and function of the mutated protein.Methods: A Chinese family with XP,including two affected individuals and four family members with normal phenotype,were recruited.Whole-exome sequencing was performed on a proband’s blood sample to identify POLH mutation sites.Sanger sequencing was used to validate the mutations in saliva or blood samples from the affected individuals and the normal individuals.The structure and function of the mutated protein were predicted using Mutation Taster,Swiss-Model,and Alpha Fold2.Results: A homozygous deletion mutation of exon 8 of the POLH gene on chromosome 6(NM＿001291969: c.791 del C)was found in both patients,resulting in XPV.Bioinformatic analysis indicated that this mutation is deleterious to protein function and may lead to truncation of the encoded protein.Conclusion: We report a novel XPV family with a new POLH gene mutation.Our study expands the spectrum of mutations associated with XPV.