Identification of Two Novel Mutations in Exon 2 of the Bmp15 Gene in Infertile Pakistani Females

Abstract

Female reproductive lifespan, marked by the timing of natural menopause, has significant implications for fertility, healthspan, and susceptibility. It has been critically evaluated the evidence for previously reported monogenic causes of premature ovarian insufficiency, demonstrating that many variants originally classified as pathogenic show substantially reduced penetrance in population-based cohorts. We have highlighted the emerging discoveries from exome-wide association studies, including novel genes such as ZNF518A, ETAA1, and SAMHD1 that harbor rare variants with large effects on menopause timing. We explore the pleiotropic effects of reproductive ageing genes on cancer susceptibility, particularly the trade-off between later menopause and increased malignancy risk mediated by SAMHD1 and CHEK2. Finally, we discussed clinical implications, including the reclassification of genetic variants, the potential for polygenic risk scoring, and the need for population-specific studies to address global diversity in reproductive ageing genetics.