Genetics of Premature Ovarian Insufficiency: From Molecular Architecture to Precision Medicine

Abstract

Premature ovarian insufficiency (POI) affects 1–3.7% of women and causes infertility and long-term morbidity. Next-generation sequencing has identified more than 130 POI-associated genes. The diagnostic yield of genetic testing depends on cohort size and the quality and scope of the genetic analysis, reaching 29.3% in our largest international cohort reported to date. Major biological pathways involve meiosis/DNA repair, follicular growth, and mitochondrial/metabolic functions. Meiosis/DNA-repair defects can impair fetal establishment of the ovarian reserve and, depending on the gene, variant, and allelic state, may be associated with chromosomal instability or cancer predisposition. This could enable early identification of selected at-risk patients, oncogenetic assessment, and cancer-prevention strategies. In contrast, alterations affecting follicular growth, metabolism, or mitochondrial function may be associated with persistence of a residual follicular pool, revealing a limited window of opportunity for timely fertility preservation in selected patients and at-risk relatives. Genetic diagnosis provides actionable information for etiological classification, and can reveal a syndromic condition, guide family screening, and, in selected genotypes, inform comorbidity assessment and early fertility preservation. It may also guide future mechanism-based therapies. By translating molecular findings into individualized reproductive and long-term care, POI provides a paradigmatic model of precision medicine in female infertility and reproductive endocrinology.