Point-of-care whole-exome sequencing of idiopathic male infertility

Khalid Adnan Mohamed A. Fakhro, Haitham Elbardisi, Mohamed Arafa, Amal Robay, Juan L. Rodriguez-Flores, Alya Al-Shakaki, Najeeb Syed, Jason G. Mezey, Charbel Abi Khalil, Joel Malek, Abdulla Al-Ansari, Sami Al Said, Ronald Crystal

Research output: Contribution to journalArticle

9 Citations (Scopus)


Purpose: Nonobstructive azoospermia (NOA) affects 1% of the male population; however, despite state-of-the-art clinical assessment, for most patients the cause is unknown. We capitalized on an analysis of multiplex families in the Middle East to identify highly penetrant genetic causes. Methods: We used whole-exome sequencing (WES) in 8 consanguineous families and combined newly discovered genes with previously reported ones to create a NOA gene panel, which was used to identify additional variants in 75 unrelated idiopathic NOA subjects and 74 fertile controls. Results: In five of eight families, we identified rare deleterious recessive variants in CCDC155, NANOS2, SPO11, TEX14, and WNK3 segregating with disease. These genes, which are novel to human NOA, have remarkable testis-specific expression, and murine functional evidence supports roles for them in spermatogenesis. Among 75 unrelated NOA subjects, we identified 4 (~5.3%) with additional recessive variants in these newly discovered genes and 6 with deleterious variants in previously reported NOA genes, yielding an overall genetic etiology for 13.3% subjects versus 0 fertile controls (p = 0.001). Conclusion: NOA affects millions of men, many of whom remain idiopathic despite extensive laboratory evaluation. The genetic etiology for a substantial fraction of these patients (>50% familial and >10% sporadic) may be discovered by WES at the point of care.

Original languageEnglish
Pages (from-to)1365-1373
Number of pages9
JournalGenetics in Medicine
Issue number11
Publication statusPublished - 1 Nov 2018



  • disease genetics
  • male infertility
  • nonobstructive azoospermia
  • spermatogenic failure
  • whole-exome sequencing

ASJC Scopus subject areas

  • Genetics(clinical)

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