MP76-06 WHOLE-EXOME SEQUENCING IDENTIFIES NOVEL HOMOZYGOUS MUTATION IN NPAS2 IN FAMILY WITH NONOBSTRUCTIVE AZOOSPERMIA

Abstract

You have accessJournal of UrologyInfertility: Basic Research, Physiology, Pathophysiology1 Apr 2015MP76-06 WHOLE-EXOME SEQUENCING IDENTIFIES NOVEL HOMOZYGOUS MUTATION IN NPAS2 IN FAMILY WITH NONOBSTRUCTIVE AZOOSPERMIA Ranjith Ramasamy, Emre Bakircioglu, Cenk Cengiz, Ender Karaca, Jason Scovell, Matthew Bainbridge, James Lupski, and Dolores Lamb Ranjith RamasamyRanjith Ramasamy More articles by this author , Emre BakirciogluEmre Bakircioglu More articles by this author , Cenk CengizCenk Cengiz More articles by this author , Ender KaracaEnder Karaca More articles by this author , Jason ScovellJason Scovell More articles by this author , Matthew BainbridgeMatthew Bainbridge More articles by this author , James LupskiJames Lupski More articles by this author , and Dolores LambDolores Lamb More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2791AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Nonobstructive azoospermia (NOA) is characterized by lack of sperm in the ejaculate due to severe testicular failure. Due to genetic and clinical heterogeneity, the diagnosis is not straightforward. Current clinical practices have focused on karyotype and microdeletions. In the present study, we investigated the genetic cause of NOA in a consanguineous Turkish family through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations. METHODS We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the Illumina HiSeq 2000 next-generation sequencing platform. We sequenced the exomes of two affected siblings. Exome analysis resulted in the identification of 442 variants in the index patients. All variants that passed filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. RESULTS A novel non-synonymous mutation in neuronal PAS 2 domain (NPAS2) was identified in a consanguineous family from Turkey. This mutation in exon 14 (chr2: 101592000 C>G) of NPAS2 segregates with the disease. Family segregation of the variants showed the presence of homozygous mutation in the three brothers with NOA and heterozygous mutation in one brother, and one sister who were fertile. The mutation is not found in the single nucleotide polymorphism (SNP) database, the 1000 Genomes Project, Baylor College of Medicine cohort of 500 Turkish patients (not a founder mutation) or matching 50 fertile controls. The absence of homozygous mutations in NPAS2 in these databases suggests that such gene perturbations are not consistent with fertility, and therefore the observed NPAS2 mutation is considered likely to be pathogenic. CONCLUSIONS Using WES, we identified a novel homozygous mutation in NPAS2 as a likely disease-causing variant in three brothers with NOA. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e985-e986 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ranjith Ramasamy More articles by this author Emre Bakircioglu More articles by this author Cenk Cengiz More articles by this author Ender Karaca More articles by this author Jason Scovell More articles by this author Matthew Bainbridge More articles by this author James Lupski More articles by this author Dolores Lamb More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...