Dataset Information

Identification of rare paired box 3 variant in strabismus by whole exome sequencing.

ABSTRACT: AIM:To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS:A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS:Whole exome sequencing and filtering identified a nonsynonymous mutation c.434G-T transition in paired box 3 (PAX3) in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION:Our results report that the c.434G-T mutation (p.R145L) in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.

SUBMITTER: Gong HM

PROVIDER: S-EPMC5554839 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Identification of rare paired box 3 variant in strabismus by whole exome sequencing.

Gong Hui-Min HM Wang Jing J Xu Jing J Zhou Zhan-Yu ZY Li Jing-Wen JW Chen Shu-Fang SF

International journal of ophthalmology 20170818 8

<h4>Aim</h4>To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus.<h4>Methods</h4>A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing.<h ...[more]

PMID: 28861346

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Project description:Background:Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Methods:Using 11?990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided. Results:Strong signals were detected for CDKN2A (Pmin = 6.16?×?10-8) in the CM cohort (n?=?273) and BAP1 (Pmin = 3.83?×?10-6) in the OM (n?=?99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379?CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75?×?10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37?×?10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. Conclusions:The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.

Dataset Information

Identification of rare paired box 3 variant in strabismus by whole exome sequencing.

Publications

Identification of rare paired box 3 variant in strabismus by whole exome sequencing.

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