|Title||Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Ramasamy, R, M Bakırcıoğlu, E, Cengiz, C, Karaca, E, Scovell, J, Jhangiani, SN, Akdemir, ZC, Bainbridge, M, Yu, Y, Huff, C, Gibbs, RA, Lupski, JR, Lamb, DJ|
|Date Published||2015 Aug|
|Keywords||Adult, Azoospermia, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Exome, Homozygote, Humans, Male, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Pedigree|
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.
|Alternate Journal||Fertil. Steril.|
|PubMed Central ID||PMC4522373|
|Grant List||U54 HG006542 / HG / NHGRI NIH HHS / United States |
R01NS058529 / NS / NINDS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
K12 HD073917 / HD / NICHD NIH HHS / United States
HD073917-01 / HD / NICHD NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
5 U54 HG003273 / HG / NHGRI NIH HHS / United States