A genomics approach to male infertility



Male infertility remains poorly understood at the molecular level. We aimed in this study to investigate the yield of a “genomics first” approach to male infertility.


Patients with severe oligospermia and nonobstructive azoospermia were investigated using exome sequencing (ES) in parallel with the standard practice of chromosomal analysis.


In 285 patients, 10.5% (n = 30) had evidence of chromosomal aberrations while nearly a quarter (n = 69; 24.2%) had a potential monogenic form of male infertility. The latter ranged from variants in genes previously reported to cause male infertility with or without other phenotypes in humans (24 patients; 8.4%) to those in novel candidate genes reported in this study (37 patients; 12.9%). The 33 candidate genes have biological links to male germ cell development including compatible mouse knockouts, and a few (TERB1 [CCDC79], PIWIL2, MAGEE2, and ZSWIM7) were found to be independently mutated in unrelated patients in our cohort. We also found that male infertility can be the sole or major phenotypic expression of a number of genes that are known to cause multisystemic manifestations in humans (n = 9 patients; 3.1%).


The standard approach to male infertility overlooks the significant contribution of monogenic causes to this important clinical entity.

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We thank the study families for their enthusiastic participation. We also thank the Sequencing Core Facility at KFSHRC for their technical help.

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Corresponding authors

Correspondence to Wafa Qabbaj PhD or Fowzan S. Alkuraya MD.

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The authors declare no conflicts of interest.

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Co-first authors: Naif Alhathal, Sateesh Maddirevula, Serdar Coskun

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Alhathal, N., Maddirevula, S., Coskun, S. et al. A genomics approach to male infertility. Genet Med (2020). https://doi.org/10.1038/s41436-020-0916-0

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  • azoospermia
  • oligospermia
  • reverse phenotyping
  • Y-chromosome microdeletion