A genomics approach to male infertility

Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.


Purpose: 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.

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

Results: 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%).

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

Keywords: Y-chromosome microdeletion; azoospermia; oligospermia; reverse phenotyping.

MeSH terms

  • Animals
  • Argonaute Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • Chromosome Deletion
  • Chromosomes, Human, Y
  • Genomics
  • Humans
  • Infertility, Male* / genetics
  • Male
  • Mice
  • Oligospermia* / genetics
  • Sex Chromosome Aberrations


  • Argonaute Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • PIWIL2 protein, human
  • TERB1 protein, mouse