Exploring the Potential of Exome Sequencing in Idiopathic Azoospermia: A Genetic Burden and Network Analysis Study

Baiba Alkšere (Coresponding Author), Agrita Puzuka, Marija Lazovska, Ninel Miriam Vainselbaum, Janis Kristaps Vasilonoks, Elvita Penka, Violeta Fodina, Juris Ērenpreiss

Research output: Contribution to journalArticlepeer-review


The purpose of this study was to investigate the linkage of the association of azoospermia phenotype with genetic alterations, involved in genome instability. Male infertility is a multifactorial pathology, and genetic alterations might be the underlying factors in majority of cases of severe male infertility. The recent emergence of next-generation sequencing offers an opportunity to analyze many genes and their interactions at once, and whole-exome sequencing (WES) together with whole-genome sequencing (WGS) was recently suggested for implementation of diagnosis workup in severe infertility cases. However, the reports on WES in conjunction with burden tests and gene network analysis are scarce or lacking in cases of severe male infertility. WES was performed on 21 nonobstructive azoospermia patients. DNA samples were sequenced using the Twist Comprehensive Exome Panel. Genetic burden test was performed with Testing Rare vAriants using Public Data. Protein interactions were investigated with ConsensusPathDB and Cytoscape. For single nucleotide variants and copy number variations (CNV) analysis, samples were analyzed with the Illumina's BaseSpace Variant Interpreter. Genetic variant burden was found elevated in 1,473 genes out of 30,000 known testis expressed genes. Three hundred and two genes with increased loss-of-function (LoF) variant set were present in more than one sample. Overrepresentation analysis with pathway-based set of genes with high variant burden demonstrated 26 pathways. Overrepresentation analysis with protein complex-based gene sets obtained 14 sets, showing the involvement in cell proliferation and DNA repair. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) network analysis with Cytoscape identified two clusters: (1) genes, involved in DNA binding/condensation and repair processes and (2) genes with the role in ribosome biosynthesis and gene expression processes. Increased loss of function germline variant burden and sumoylation may have critical significance in spermatogenesis. These parameters may be used for focused diagnosis in nonobstructive azoospermia patients. This may have both general significance for the decreased organism functionality but in particular is critical in spermatogenesis.

Original languageEnglish
Article number 3107568
Number of pages12
Publication statusPublished - 17 Aug 2023

Field of Science*

  • 3.1 Basic medicine

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database


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