Genetic Factors in Male Infertility

Male infertility is a complex condition influenced by a spectrum of genetic factors ranging from chromosomal abnormalities and Y-chromosome microdeletions to single-gene mutations and polygenic risk variants. Disruptions of spermatogenesis may arise from defects in DNA packaging, chromatin remodelling, hormone regulation and epigenetic modifications. Common polymorphisms in folate-metabolising enzymes can alter DNA methylation and nucleotide synthesis, while variants in protamine and DAZL genes affect sperm chromatin compaction and germ-cell differentiation. Rare, high-impact mutations revealed by whole-exome sequencing account for specific morphological phenotypes such as globozoospermia and macrozoospermia. Copy-number variations and loss-of-function alleles further contribute to diverse presentations, including oligozoospermia and non-obstructive azoospermia. Advances in high-throughput sequencing and meta-analytic methods have refined genotype–phenotype correlations, informing genetic counselling, prognosis and personalised assisted-reproduction strategies. The global burden of male infertility emphasises the need for comprehensive genetic screening panels and translational research to guide clinical decision-making and to identify novel therapeutic targets.

Research from Nature Portfolio

Large-scale meta-analyses have clarified the role of common polymorphisms in one-carbon metabolism, chromatin structure and germ-cell development. A comprehensive aggregation of case-control studies demonstrated that the MTHFR C677T variant significantly increases susceptibility to oligo- and azoospermia, particularly in Asian populations, whereas other folate-pathway mutations showed inconsistent associations. A parallel synthesis of protamine 1 and protamine 2 polymorphisms identified a promoter substitution in the PRM2 gene as a consistent risk factor for male infertility, with certain alleles exerting protective effects in specific ethnic groups. Another meta-analysis of DAZL gene variants employed trial sequential analysis to distinguish false positives from genuine risk alleles, confirming a significant association of the T54A polymorphism with impaired sperm parameters in Asian cohorts. Together, these studies underscore the multifactorial nature of genetic risk and highlight the necessity of rigorous statistical validation to delineate true disease-causing variants.

Genetic Factors in Male Infertility publication trend

The graph below shows the total number of articles in genetic factors in male infertility across all publications each year (not limited to Nature Index journals).

Technical terms

Spermatogenesis: The multi-stage development of haploid spermatozoa from germ stem cells within the seminiferous tubules.

Oligozoospermia: A condition defined by reduced sperm concentration in the ejaculate below established reference values.

Azoospermia: The complete absence of spermatozoa in a semen sample, indicative of severe spermatogenic failure or obstruction.

Single nucleotide polymorphism (SNP): A single-base variation in the genome that may affect gene function, expression or protein structure.

Meta-analysis: A quantitative technique that pools data from multiple independent studies to derive a combined estimate of effect size.

Loss-of-function variant: A genetic alteration resulting in reduced or abolished activity of the encoded protein, often leading to disease phenotypes.

Whole-exome sequencing (WES): A genomic approach that selectively sequences all protein-coding regions to identify rare and common variants linked to disease.

References

1. Biomarkers of Iron Are Associated with Anterior-Pituitary-Produced Reproductive Hormones in Men with Infertility. Nutrients (2024).
2. A loss-of-function variant in ZCWPW1 causes human male infertility with sperm head defect and high DNA fragmentation. Reproductive Health (2024).
3. Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia. Human Reproduction (2020).
4. Polymorphisms in Protamine 1 and Protamine 2 predict the risk of male infertility: a meta-analysis. Scientific Reports (2015).
5. Association between DAZL polymorphisms and susceptibility to male infertility: systematic review with meta-analysis and trial sequential analysis. Scientific Reports (2014).
6. Whole-exome sequencing identified a novel mutation of AURKC in a Chinese family with macrozoospermia. Journal of Assisted Reproduction and Genetics (2018).
7. MTHFR C677T, A1298C and MS A2756G Gene Polymorphisms and Male Infertility Risk in a Chinese Population: A Meta-Analysis. PLOS ONE (2017).