title: Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia.
abstract: OBJECTIVE
  To investigate the genetic cause of nonobstructive azoospermia (NOA) in a consanguineous Turkish family through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations.
  
  
  METHODS
  Whole-exome sequencing (WES).
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Two siblings in a consanguineous family with NOA.
  
  
  METHODS
  Validating all variants passing filter criteria with Sanger sequencing to confirm familial segregation and absence in the control population.
  
  
  METHODS
  Discovery of a mutation that could potentially cause NOA.
  
  
  RESULTS
  A novel nonsynonymous mutation in the neuronal PAS-2 domain (NPAS2) was identified in a consanguineous family from Turkey. This mutation in exon 14 (chr2: 101592000 C>G) of NPAS2 is likely a disease-causing mutation as it is predicted to be damaging, it is a novel variant, and it segregates with the disease. Family segregation of the variants showed the presence of the homozygous mutation in the three brothers with NOA and a heterozygous mutation in the mother as well as one brother and one sister who were both fertile. The mutation is not found in the single-nucleotide polymorphism database, the 1000 Genomes Project, the Baylor College of Medicine cohort of 500 Turkish patients (not a population-specific polymorphism), or the matching 50 fertile controls.
  
  
  CONCLUSIONS
  With the use of WES we identified a novel homozygous mutation in NPAS2 as a likely disease-causing variant in a Turkish family diagnosed with NOA. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases for which conventional genetic approaches have previously failed to find a molecular diagnosis.
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas; Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Ranjith
authors.initials: R
authors.lastname: Ramasamy
authors.affiliation: Private practice, Istanbul, Turkey.
authors.forename: M Emre
authors.initials: ME
authors.lastname: Bakırcıoğlu
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas; Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Cenk
authors.initials: C
authors.lastname: Cengiz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas.
authors.forename: Jason
authors.initials: J
authors.lastname: Scovell
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Zeynep C
authors.initials: ZC
authors.lastname: Akdemir
authors.affiliation: Codified Genomics, Houston, Texas.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bainbridge
authors.affiliation: Department of Epidemiology, MD Anderson Cancer Center, University of Texas, Houston, Texas.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Epidemiology, MD Anderson Cancer Center, University of Texas, Houston, Texas.
authors.forename: Chad
authors.initials: C
authors.lastname: Huff
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas; Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas. Electronic address: dlamb@bcm.edu.
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Lamb
mesh_terms: D000328:Adult; D053713:Azoospermia / Q000175:diagnosis* / Q000235:genetics*; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C104264:NPAS2 protein, human
keywords: Circadian rhythm; consanguineous; genome; male infertility; spermatogenesis