Genetic and Epigenetic Risks of Male Infertility in ART

Assisted reproductive technologies (ART) and, in particular, intracytoplasmic sperm injection (ICSI) transformed the management of male infertility by making fertility possible in previously untreatable cases. However, the bypassing of natural selection mechanisms at fertilization is fraught with the danger of transmission of genetic and epigenetic abnormalities. Male infertility is now a multifactorial disorder with notable contributions from single-gene defects, chromosomal abnormalities, and Y-chromosome microdeletions. The recent advances in next-generation sequencing and sperm omics have identified mutations and copy-number variations in genes critical for spermatogenesis, flagellar structure, and endocrine regulation. Along with these findings, an increasing body of evidence suggests that ART procedures can lead to a disruption of epigenetic reprogramming during gametogenesis and early embryogenesis, resulting in imprinting disorders and altered patterns of gene expression in the offspring. This review synthesizes recent progress in the molecular underpinnings of genetic and epigenetic hazards of ART, with an emphasis on clinical significance for reproductive counselling and ethical considerations for future generations.