The genetic insights of sporadic male infertility: a systematic review of WES and WGS studies (2014–2024)

Abstract

Male infertility is a complex and heterogeneous disorder. It has a significant genetic component, although some cases remain idiopathic. Next-generation sequencing, particularly whole-exome (WES) and whole-genome sequencing (WGS) has become a powerful tool for uncovering new genetic causes. This systematic review aimed to identify and synthesize genes linked to male infertility reported in WES or WGS studies. The review was registered on PROSPERO (CRD42024597301). A bibliographic search was conducted on PubMed, Scopus, and Web of Science (2014-2024). We included human studies that used WES or WGS to investigate the genetics of male infertility. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment with JBI checklists. Out of 8018 identified records, 23 studies met the inclusion criteria. In total, 169 unique genes were reported; after removing duplicates, 143 genes remained. The most frequently implicated phenotypes were multiple morphological abnormalities of the flagella (MMAF) and non-obstructive azoospermia (NOA). Genes were stratified by recurrence across independent cohorts and by functional validation status. Of the 143 genes, five were replicated with functional validation, 22 demonstrated either replication or functional validation, and 116 were reported in single studies with only in silico support. In studies applying the criteria of American College of Medical Genetics and Genomics (ACMG), the diagnostic yield was 48% for MMAF and 12-23% for NOA, with an average variant-of-uncertain-significance (VUS) burden of 47%. ACMG classification was inconsistently applied across studies. MMAF-associated genes were predominantly autosomal recessive (95%), whereas NOA-associated genes exhibited greater diversity: 60% autosomal recessive, 25% X-linked, and 15% autosomal dominant. Only 34% of genes had undergone functional validation. In summary, among WES and WGS studies of predominantly sporadic cohorts, most identified genes were reported in single studies without functional validation, and standardized variant classification was implemented in only a minority of studies.