Infertility affects an estimated 48 million couples and 186 million individuals worldwide. Premature ovarian insufficiency (POI), alongside generalized late marriage and childbirth, is one among many factors contributing to infertility. The causes of POI are heterogeneous, and genetic abnormalities, including chromosome number abnormalities and single-gene mutations, account for up to 30% of all POI cases. However, recent studies have suggested that the predictive power of individual gene mutations for the onset of premature ovarian insufficiency is weak, and the collaborative pathogenecity of double or multiple mutations is instead more likely to cause the phenotype in POI individuals. Nevertheless, current experiences about double mutations in POI individuals or families remain relatively limited.
We identified a family with a Premature ovarian insufficiency (POI) history. The family has several POI individuals. However, by whole exon sequencing(WES), we didn’t identify a single gene mutation that was directly associated with the disease phenotype. Instead, we find that the affected individuals share two mutations in which one is more scarce and the other is more common(frequency > 0.1%) among the general population. We suppose the two mutations might act synergistically to cause the POI phenotype. To verify this hypothesis, we want to use the UK biobank to examine whether this mutation pair is significantly associated with early menopause.
The project will last for 36 months.The investigation aims to elucidate whether the co-occurrence of these mutations is significantly associated with early menopause. This approach recognizes the complexity of genetic contributions to POI, moving beyond the traditional focus on single-gene mutations. By investigating the correlation of paired gene mutations with female reproductive longevity, we will contribute to current understanding of the genetics of POI, and help to reveal new therapeutic targets for infertility.
