The Genetic Landscape of Human Infertility: A Comprehensive Review

Background: Infertility affects approximately one in seven couples worldwide and arises from a heterogeneous interplay of chromosomal abnormalities, monogenic defects, polygenic susceptibility, epigenetic dysregulation, mitochondrial dysfunction, and environmental factors, yet a large proportion of cases still lack a clearly defined genetic etiology. Objective: To synthesize current evidence on the genetic, epigenetic, and mitochondrial determinants of male and female infertility, and to examine how these discoveries inform diagnostic evaluation, clinical management, and ethical, legal, and social frameworks. Methods: A narrative review of the literature was conducted using searches of major biomedical databases and targeted snowballing to identify original research, reviews, and professional guidelines on chromosomal, monogenic, polygenic, epigenetic, and mitochondrial mechanisms in human infertility, as well as their clinical translation into genetic testing, preimplantation genetic testing, and counseling. Results: Sex-chromosome aneuploidies, Y-chromosome microdeletions, and an expanding set of monogenic defects explain substantial fractions of severe male factor infertility and primary ovarian insufficiency, while GWAS have revealed complex polygenic architectures for polycystic ovary syndrome and endometriosis. Epigenetic and mitochondrial perturbations influence gamete competence and ART outcomes, and genetic testing and preimplantation genetic testing are increasingly embedded in guidelines, though access, variant interpretation, and ethical concerns remain challenging. Conclusion: The genetic landscape of human infertility is broad and rapidly evolving; integrating chromosomal, monogenic, polygenic, epigenetic, and mitochondrial insights into personalized reproductive care requires continued gene discovery, multi-ancestry research, robust counseling, and ethically grounded policy.