Genetic variants in diminished ovarian reserve and premature ovarian insufficiency: implications for assisted reproductive outcomes

To investigate the genetic factors underlying diminished ovarian reserve (DOR) and premature ovarian insufficiency (POI) in 55 infertile women of reproductive age in China and to evaluate the outcomes of assisted reproductive technology (ART) treatment in cases of genetically associated DOR/POI.

Whole-exome sequencing was performed to identify pathogenic gene variants associated with DOR and POI. Clinical data were systematically collected and analyzed.

Biallelic or heterozygous variants in 15 genes associated with the pathogenesis of these conditions were identified in 20/55 patients with DOR or POI. These genes are involved in the following four key biological processes: meiosis (SYCE1, C14orf39, MSH4, MSH5, MCM9, NBN, REC114, WRN, BNC1, and HFM1), transcriptional regulation (TBPL2, EIF2B5, and NOBOX), mitochondrial function (TWNK), and granulosa cell formation and development (UMODL1). Novel variants accounted for 76% of all identified variants. The parental origin of these variants was confirmed through Sanger sequencing, and AlphaFold analysis demonstrated structural abnormalities in the affected proteins caused by the identified missense variants. Retrospective analyses of ART outcomes revealed that younger patients had more favorable prognostic outcomes than older patients.

POI/DOR-associated genetic defects were classified into four functional pathways, with meiotic variants emerging as key drivers of poor ART outcomes, whereas granulosa cell-related variants were associated with favorable prognoses. Younger age was identified as a potential positive factor for clinical success, highlighting the need for validation in larger cohorts to refine variant- and age-specific treatment strategies. These findings provide valuable insights for tailoring treatment based on genetic variants.