Detection Of POLH Gene Mutation In A Family With Xeroderma Pigmentosum

Background: Xeroderma pigmentosum(XP,OMIM#278700-278780)is a rare autosomal recessive disorder,described as early as 1870,which is characterized by a high sensitivity to sunlight,leading to sunburn,pigment changes in the skin and significant increasing the incidence of a variety of skin cancers.It has been found in all continents and ethnic racial groups with a reported incidence of approximately2.3:1,000,000 in Western Europe,while higher incidences compared to Japan(1:20,000),North Africa,Pakistan,and the Middle East.About three fifths of affected individuals show severe and long-term sunburn reactions,while others show an increase number of lentigines in light-exposed sites which are clinically difficult to distinguish from many other pigmented diseases.Besides,nervous system disorders and mental retardation occur in about one-quarter of patients.The clinical characteristics and pathology are related to exposure to sunlight,the genes involved,the type of mutation on this gene,the ethnicity of the XP patients.There are currently eight XP complementation groups and their corresponding genes [XP-A(XPA),XP-B(ERCC3),XP-C(XPC),XP-D(ERCC2),XP-E(DDB2),XP-F(ERCC4),XP-G(ERCC5)and XP-V(POLH)] linked to XP.Among them,XPA–XPG are involved in the repair of UV-induced photoproducts in DNA through the process of nucleotide excision repair(Nucleotide excision repair,NER).The translesional DNA polymerase(XP-V or DNA polymerase η)is almost normal in NER but has defects in repair after replication.At present,scholars at home and abroad have detected almost 100 mutations in the POLH gene in different XP families that are related to XP,accounting for about a quarter of XP.The mutation types of POLH gene include single base substitution(missense mutation and nonsense mutation),splicing mutations,deletions or insertion mutations.Most of them are deletions or lead to stop codons.However,no clear mutation hotspot and clear correlation between genotype and phenotype have been found.Objective(1)Report the POLH gene mutation in a Chinese Han XP family and analyze the clinical and genetic characteristics of the family.(2)Review and summarize the POLH gene mutation cases and describe their mutation characteristics previously reported.Methods1.Collect peripheral blood samples of two Chinese Han XP patients and their family members.The proband was sequenced by next-generation sequencing(next-generation sequencing,NGS),and the remaining relatives were verified by Sanger sequencing.The sequences were compared with the UCSC human genome reference(GRCh37/hg19),DNA Sequencing analysis software is used to analyze the results,and software such as Mutation Taster is used to perform function prediction.2.We analyzed and summarized POLH gene mutation cases reported at domestic and abroad by searching the HGMD and Pub Med databases.Results1.A nonsense mutation(c.1066C>T,p.Arg356Ter)in exon 9 of the POLH gene(NM＿006502.2)was found in the affected patients,at the same time,the proband has a large deletion in exon 5 to exon 8 of the POLH gene,which did not indicate in the unaffected family members and the reference sequence.The clinically affected manifestations are similar to previously reported POLH mutation in XP patients.2.The literature review summarized the general clinical characteristics of XPV patients as symptoms of school age,milder clinical manifestations,and late diagnosis.A total of84 XP pathogenic mutation in the POLH gene has been reported so far(nonsense mutations accounting for 20.2%,missense mutations accounting for 25.0%,splicing mutations accounting for 9.5%,insertion mutations accounting for 11.9%,and deletion mutations accounting for 33.3%).Conclusions1.The proband was found and reported for the first time in the del exon5-8 with a large deletion of the POLH gene;a nonsense mutation in exon 9 of the POLH gene(c.1066C> T,p.Arg356Ter)was previously reported abroad,which may be the main reason for the clinical manifestations of two XP patients in this family.2.It is found that single-base substitutions and deletion mutations occupy most of the mutation types of POLH gene.