Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia

Ranjith Ramasamy, M. Emre Bakircioʇlu, Cenk Cengiz, Ender Karaca, Jason Scovell, Shalini N. Jhangiani, Zeynep C. Akdemir, Matthew Bainbridge, Yao Yu, Chad Huff, Richard A. Gibbs, James R. Lupski, Dolores J. Lamb

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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. Design Whole-exome sequencing (WES). Setting Research laboratory. Patient(s) Two siblings in a consanguineous family with NOA. Intervention(s) Validating all variants passing filter criteria with Sanger sequencing to confirm familial segregation and absence in the control population. Main Outcome Measure(s) Discovery of a mutation that could potentially cause NOA. Result(s) 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. Conclusion(s) 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.

Original languageEnglish (US)
Pages (from-to)286-291
Number of pages6
JournalFertility and sterility
Issue number2
StatePublished - Aug 1 2015
Externally publishedYes


  • Circadian rhythm
  • consanguineous
  • genome
  • male infertility
  • spermatogenesis

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology


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