Genetic landscape of primary ovarian insufficiency in Bangladeshi women through whole exome sequencing.

Abstract

Background: Primary Ovarian Insufficiency (POI), a significant cause of female infertility, involves premature ovarian dysfunction before the age of 40 and is influenced by genetic predispositions, autoimmune disorders, environmental factors, and metabolic changes. In this study, we employed Whole Exome Sequencing (WES) to explore genetic variations linked to POI in Bangladeshi women.

Materials and methods: This study encompassed 30 Bangladeshi women aged 16 to 40 diagnosed with POI. The diagnosis was based on clinical criteria, including elevated Follicle-Stimulating Hormone levels and a history of at least four months of oligomenorrhea or amenorrhea. WES was performed on POI cases and used population specific internal cohort to filter out and identify genes impacting ovarian function. Subsequently, Sanger Sequencing was used to validate pathogenic or likely pathogenic variants.

Results: We detected seven pathogenic variants in 23% of all POI cases (7/30) across six genes: Thyroglobulin (TG), Thyroid-Stimulating Hormone Receptor (TSHR), tubulin beta 8 class viii (TUBB8), PR/SET domain 9 (PRDM9), required for meiotic nuclear division 1 homolog (RMND1), and homologous recombination factor with OB-fold (HROB). Two novel likely pathogenic variants were identified, including a heterozygous frameshift variant in TG (p.H209Pfs11) and a heterozygous missense variant in TSHR (p.T1904C). Additionally, variants of uncertain significance were found in 63% (19/30) of the cases, with seven being novel. Incidental findings of pathogenic variants were observed in several genes, with Hemoglobin subunit Beta (HBB) being the most common.

Conclusions: This study highlights the utility of whole exome sequencing in identifying genetic risk factors for POI, suggesting that incorporating genetic screening into routine clinical practice could improve diagnostic and therapeutic strategies, particularly in regions lacking genomic data on this condition.