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Whole-exome sequencing enables rapid determination of xeroderma pigmentosum molecular etiology.

ABSTRACT: Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme sensitivity to actinic pigmentation changes in the skin and increased incidence of skin cancer. In some cases, patients are affected by neurological alterations. XP is caused by mutations in 8 distinct genes (XPA through XPG and XPV). The XP-V (variant) subtype of the disease results from mutations in a gene (XPV, also named POLH) which encodes for Pol?, a member of the Y-DNA polymerase family. Although the presence and severity of skin and neurological dysfunctions differ between XP subtypes, there are overlapping clinical features among subtypes such that the sub-type cannot be deduced from the clinical features. In this study, in order to overcome this drawback, we undertook whole-exome sequencing in two XP sibs and their father. We identified a novel homozygous nonsense mutation (c.897T>G, p.Y299X) in POLH which causes the disease. Our results demonstrate that next generation sequencing is a powerful approach to rapid determination of XP genetic etiology.

SUBMITTER: Ortega-Recalde O

PROVIDER: S-EPMC3670841 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Whole-exome sequencing enables rapid determination of xeroderma pigmentosum molecular etiology.

Ortega-Recalde Oscar O Vergara Jéssica Inés JI Fonseca Dora Janeth DJ Ríos Xiomara X Mosquera Hernando H Bermúdez Olga María OM Medina Claudia Liliana CL Vargas Clara Inés CI Pallares Argemiro Enrique AE Restrepo Carlos Martín CM Laissue Paul P

PloS one 20130603 6

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme sensitivity to actinic pigmentation changes in the skin and increased incidence of skin cancer. In some cases, patients are affected by neurological alterations. XP is caused by mutations in 8 distinct genes (XPA through XPG and XPV). The XP-V (variant) subtype of the disease results from mutations in a gene (XPV, also named POLH) which encodes for Polη, a member of the Y-DNA polymerase family. Although th ...[more]

PMID: 23755135

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Project description:A 17-year-old female Korean patient (XP115KO) was previously diagnosed with Xeroderma pigmentosum group C (XPC) by Direct Sanger sequencing, which revealed a homozygous nonsense mutation in the XPC gene (rs121965088: c.1735C > T, p.Arg579Ter). While rs121965088 is associated with a poor prognosis, our patient presented with a milder phenotype. Hence, we conducted whole-exome sequencing in the patient and her family members to detect coexisting mutations that may have resulted in a milder phenotype of rs121965088 through genetic interaction. Materials and Methods: the whole-exome sequencing analysis of samples obtained from the patient and her family members (father, mother, and brother) was performed. To identify the underlying genetic cause of XPC, the extracted DNA was analyzed using Agilent's SureSelect XT Human All Exon v5. The functional effects of the resultant variants were predicted using the SNPinfo web server, and structural changes in the XPC protein using the 3D protein modeling program SWISS-MODEL. Results: Eight biallelic variants, homozygous in the patient and heterozygous in her parents, were detected. Four were found in the XPC gene: one nonsense variant (rs121965088: c.1735C > T, p.Arg579Ter) and three silent variants (rs2227998: c.2061G > A, p. Arg687Arg; rs2279017: c.2251-6A > C, intron; rs2607775: c.-27G > C, 5'UTR). The remaining four variants were found in non-XP genes, including one frameshift variant [rs72452004 of olfactory receptor family 2 subfamily T member 35 (OR2T35)], three missense variants [rs202089462 of ALF transcription elongation factor 3 (AFF3), rs138027161 of TCR gamma alternate reading frame protein (TARP), and rs3750575 of annexin A7 (ANXA7)]. Conclusions: potential candidates for genetic interactions with rs121965088 were found. The rs2279017 and rs2607775 of XPC involved mutations in the intron region, which affected RNA splicing and protein translation. The genetic variants of AFF3, TARP, and ANXA7 are all frameshift or missense mutations, inevitably disturbing the translation and function of the resultant proteins. Further research on their functions in DNA repair pathways may reveal undiscovered cellular relationships within xeroderma pigmentosum.

Dataset Information

Whole-exome sequencing enables rapid determination of xeroderma pigmentosum molecular etiology.

Publications

Whole-exome sequencing enables rapid determination of xeroderma pigmentosum molecular etiology.

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