Whole-genome sequencing identifies new candidate genes for nonobstructive azoospermia

Andrology. 2022 Nov;10(8):1605-1624. doi: 10.1111/andr.13269. Epub 2022 Sep 7.


Background: Genetic causes that lead to spermatogenetic failure in patients with nonobstructive azoospermia (NOA) have not been yet completely established.

Objective: To identify low-frequency NOA-associated single nucleotide variants (SNVs) using whole-genome sequencing (WGS).

Materials and methods: Men with various types of NOA (n = 39), including samples that had been previously tested with whole-exome sequencing (WES; n = 6) and did not result in diagnostic conclusions. Variants were annotated using the Ensembl Variant Effect Predictor, utilizing frequencies from GnomAD and other databases to provide clinically relevant information (ClinVar), conservation scores (phyloP), and effect predictions (i.e., MutationTaster). Structural protein modeling was also performed.

Results: Using WGS, we revealed potential NOA-associated SNVs, such as: TKTL1, IGSF1, ZFPM2, VCX3A (novel disease causing variants), ESX1, TEX13A, TEX14, DNAH1, FANCM, QRICH2, FSIP2, USP9Y, PMFBP1, MEI1, PIWIL1, WDR66, ZFX, KCND1, KIAA1210, DHRSX, ZMYM3, FAM47C, FANCB, FAM50B (genes previously known to be associated with infertility) and ALG13, BEND2, BRWD3, DDX53, TAF4, FAM47B, FAM9B, FAM9C, MAGEB6, MAP3K15, RBMXL3, SSX3 and FMR1NB genes, which may be involved in spermatogenesis.

Discussion and conclusion: In this study, we identified novel potential candidate NOA-associated genes in 29 individuals out of 39 azoospermic males. Note that in 5 out of 6 patients subjected previously to WES analysis, which did not disclose potentially causative variants, the WGS analysis was successful with NOA-associated gene findings.

Keywords: biomarkers; infertility; nonobstructive azoospermia; spermatogenesis; whole-genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Argonaute Proteins / genetics
  • Azoospermia* / diagnosis
  • Azoospermia* / genetics
  • Calcium-Binding Proteins
  • DNA Helicases
  • Exome Sequencing
  • Humans
  • Immunoglobulins / genetics
  • Male
  • Membrane Proteins / genetics
  • Mutation
  • N-Acetylglucosaminyltransferases
  • Nuclear Proteins / genetics
  • Nucleotides
  • Transcription Factors
  • Transketolase / genetics


  • Argonaute Proteins
  • Calcium-Binding Proteins
  • IGSF1 protein, human
  • Immunoglobulins
  • Membrane Proteins
  • Nuclear Proteins
  • Nucleotides
  • PIWIL1 protein, human
  • TEX14 protein, human
  • Transcription Factors
  • VCX3A protein, human
  • WDR66 protein, human
  • ZMYM3 protein, human
  • TKTL1 protein, human
  • Transketolase
  • ALG13 protein, human
  • N-Acetylglucosaminyltransferases
  • FANCM protein, human
  • DNA Helicases

Supplementary concepts

  • Azoospermia, Nonobstructive