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Objective <p>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.</p> Methods <p>Whole-exome sequencing was performed to identify pathogenic gene variants associated with DOR and POI. Clinical data were systematically collected and analyzed.</p> Results <p>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 (<i>SYCE1</i>, <i>C14orf39</i>, <i>MSH4</i>, <i>MSH5</i>, <i>MCM9</i>, <i>NBN</i>, <i>REC114</i>, <i>WRN</i>, <i>BNC1</i>, and <i>HFM1</i>), transcriptional regulation (<i>TBPL2</i>, <i>EIF2B5</i>, and <i>NOBOX</i>), mitochondrial function (<i>TWNK</i>), and granulosa cell formation and development (<i>UMODL1</i>). 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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年9月11日

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  • Qianhua Xu,
  • Haitian Ding,
  • Yingchun Liu,
  • Dan Han,
  • Xun Xia,
  • Yuqian Li,
  • Xuan Sha,
  • Guotong Li,
  • Xiaoqing Ni,
  • Kuokuo Li,
  • Rong Hua,
  • Xiaojin He,
  • Huan Wu,
  • Yunxia Cao,
  • Yuping Xu

摘要

Objective

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.

Methods

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

Results

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.

Conclusion

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.