MP70-01 IFT140 IS A NOVEL CANDIDATE GENE FOR IMPAIRED SPERMATOGENESIS: IDENTIFICATION BY WHOLE EXOME SEQUENCING AND VALIDATION WITH SANGER SEQUENCING

Abstract

You have accessJournal of UrologyInfertility: Basic Research & Pathophysiology1 Apr 2016MP70-01 IFT140 IS A NOVEL CANDIDATE GENE FOR IMPAIRED SPERMATOGENESIS: IDENTIFICATION BY WHOLE EXOME SEQUENCING AND VALIDATION WITH SANGER SEQUENCING Amin Herati, Peter Butler, cenk Cengiz, Matthew Bainbridge, James Lupski, Richard Gibbs, Larry Lipshultz, and Dolores Lamb Amin HeratiAmin Herati More articles by this author , Peter ButlerPeter Butler More articles by this author , cenk Cengizcenk Cengiz More articles by this author , Matthew BainbridgeMatthew Bainbridge More articles by this author , James LupskiJames Lupski More articles by this author , Richard GibbsRichard Gibbs More articles by this author , Larry LipshultzLarry Lipshultz More articles by this author , and Dolores LambDolores Lamb More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1426AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES One third of male factor infertility cases are idiopathic. Many of these cases are likely caused by genetic factors. Non-obstructive azoospermia (NOA) is characterized by the absence of sperm in the ejaculate secondary to the lack of sperm production in the testicle. Advances in genetic and genomic analysis have allowed for the rapid identification of candidate genes in NOA men. The aim of our study was to identify novel variants implicated in the pathogenesis of NOA through whole-exome sequencing (WES). METHODS Homozygosity mapping with whole-exome sequencing was performed using the NimbleGen SeqCap EZ Exome V3 sample preparation kit and the Illumina HiSeq 2000 next-generation sequencing platform to sequence the exomes of two siblings with NOA from a consanguineous family. Genetic mutations that passed filter criteria were then validated using Sanger sequencing. We identified one candidate gene, Intraflagellar Transport Protein 140 (IFT140), based on its expression pattern in testes according to the Human Protein Atlas, as well the mutation′s damage prediction based on two online bioinformatic resources. We subsequently performed Sanger sequencing on 95 NOA men and 26 fertile men, all of whom were treated at our institution. RESULTS WES identified 442 variants in the index patients. Four (0.9%) of these variants passed filter criteria, one of which was a six-nucleotide deletion (HG38, chr16:1,519,961 TCTTGGC>T) in exon 22 of IFT140. Family segregation showed that this mutation was homozygous in the two brothers who underwent WES, as well as in a third brother with NOA and their sister. This mutation was not identified in the 1000 Genome Project and was predicted to be deleterious by the bioinformatics tools, MutationTaster and PROVEAN. Sanger sequencing validated the mutation in this family and identified it as a heterozygous mutation in 1 (1.1%) of the 95 NOA men and none of the 26 fertile controls in our cohort. Pathologic correlation of this unrelated patient showed hypospermatogenesis with a clinical history significant for three failed cycles of in vitro fertilization (IVF). CONCLUSIONS We have identified through WES a small indel mutation in IFT-140 as a novel, disease-causing variant. This mutation was detected in our cohort of NOA in addition to the index family assessed with a prevalence of 1.1%. Further studies are required to determine the role of IFT140 in spermatogenesis. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e905-e906 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Amin Herati More articles by this author Peter Butler More articles by this author cenk Cengiz More articles by this author Matthew Bainbridge More articles by this author James Lupski More articles by this author Richard Gibbs More articles by this author Larry Lipshultz More articles by this author Dolores Lamb More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...