• PMID: 25956372
• Gene Name: NPAS2
• Condition: Nonobstructive azoospermia (NOA)
• Association: Associated
• Population size: 2
• Population details: 2 siblings in a consanguineous family with NOA
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NPAS2
• Other associated phenotypes: Nonobstructive azoospermia (NOA)

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

Ramasamy R, Bak?rc?o?lu ME, Cengiz C, Karaca E, Scovell J, Jhangiani SN, Akdemir ZC, Bainbridge M, Yu Y, Huff C, Gibbs RA, Lupski JR, Lamb DJ.

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. CI - Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. FAU - Ramasamy, Ranjith AU - Ramasamy R AD - Scott Department of Urology, Baylor College of Medicine, Houston, Texas; Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas. FAU - Bakırcıoğlu, M Emre AU - Bakırcıoğlu ME AD - Private practice, Istanbul, Turkey. FAU - Cengiz, Cenk AU - Cengiz C AD - Scott Department of Urology, Baylor College of Medicine, Houston, Texas; Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas. FAU - Karaca, Ender AU - Karaca E AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. FAU - Scovell, Jason AU - Scovell J AD - Scott Department of Urology, Baylor College of Medicine, Houston, Texas. FAU - Jhangiani, Shalini N AU - Jhangiani SN AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. FAU - Akdemir, Zeynep C AU - Akdemir ZC AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. FAU - Bainbridge, Matthew AU - Bainbridge M AD - Codified Genomics, Houston, Texas. FAU - Yu, Yao AU - Yu Y AD - Department of Epidemiology, MD Anderson Cancer Center, University of Texas, Houston, Texas. FAU - Huff, Chad AU - Huff C AD - Department of Epidemiology, MD Anderson Cancer Center, University of Texas, Houston, Texas. FAU - Gibbs, Richard A AU - Gibbs RA AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. FAU - Lupski, James R AU - Lupski JR AD - 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.