Whole-exome sequencing of a large Chinese azoospermia and severe oligospermia cohort identifies novel infertility causative variants and genes

Hum Mol Genet. 2020 Aug 11;29(14):2451-2459. doi: 10.1093/hmg/ddaa101.


Rare coding variants have been proven to be one of the significant factors contributing to spermatogenic failure in patients with non-obstructive azoospermia (NOA) and severe oligospermia (SO). To delineate the molecular characteristics of idiopathic NOA and SO, we performed whole-exome sequencing of 314 unrelated patients of Chinese Han origin and verified our findings by comparing to 400 fertile controls. We detected six pathogenic/likely pathogenic variants and four variants of unknown significance, in genes known to cause NOA/SO, and 9 of which had not been earlier reported. Additionally, we identified 20 novel NOA candidate genes affecting 25 patients. Among them, five (BRDT, CHD5, MCM9, MLH3 and ZFX) were considered as strong candidates based on the evidence obtained from murine functional studies and human single-cell (sc)RNA-sequencing data. These genetic findings provide insight into the aetiology of human NOA/SO and pave the way for further functional analysis and molecular diagnosis of male infertility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Azoospermia / genetics*
  • Azoospermia / pathology
  • DNA Helicases / genetics
  • Exome Sequencing
  • Genetic Predisposition to Disease*
  • Humans
  • Infertility, Male / genetics*
  • Infertility, Male / pathology
  • Kruppel-Like Transcription Factors / genetics
  • Male
  • Mice
  • Minichromosome Maintenance Proteins / genetics
  • MutL Proteins / genetics
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • Oligospermia / genetics*
  • Oligospermia / pathology
  • Spermatogenesis / genetics


  • BRDT protein, human
  • Kruppel-Like Transcription Factors
  • MLH3 protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • zinc finger protein, X-linked
  • MutL Proteins
  • DNA Helicases
  • CHD5 protein, human
  • MCM9 protein, human
  • Minichromosome Maintenance Proteins

Supplementary concepts

  • Azoospermia, Nonobstructive