Genetic defects in programmed meiotic DNA double-strand break formation and repair in human infertility

In meiosis, the occurrence of programmed DNA double-strand breaks (DSBs) and their repair via homologous recombination are indispensable for homologous chromosome synapsis, crossover formation, and faithful chromosome segregation during gametogenesis. Over the past decade, advances in next-generation sequencing have expanded the spectrum of infertility-associated genes involved in meiotic DSB formation and repair, establishing this pathway as a major genetic determinant of human reproductive disorders. The disruption of these processes impairs homologous recombination and meiotic progression, leading to defective gametogenesis and a wide range of reproductive phenotypes. Clinically, genetic defects affecting meiotic DSB formation and repair have been associated with non-obstructive azoospermia in males, and a broader spectrum of reproductive phenotypes in females, such as premature ovarian insufficiency, recurrent pregnancy loss, fertilization failure, embryonic developmental arrest, recurrent hydatidiform moles, and poor outcomes following assisted reproductive technologies. This review summarizes current advances in genetic defects affecting programmed meiotic DSB formation and repair, with an emphasis on the molecular functions of disease-associated genes, evidence from animal models and genetic studies in humans, sex-dependent genotype-phenotype relationships, and their clinical relevance. Together, these advances provide a foundation for improving molecular diagnosis, genetic counseling, and precision reproductive medicine in patients with unexplained infertility.