A novel homozygous growth differentiation factor 9 variant associated with premature ovarian insufficiency: A case report.

Abstract

Background: Premature ovarian insufficiency (POI) is a condition marked by reduced ovarian function. The variants in several genes have been identified in association with POI. Growth differentiation factor 9 (GDF9) is one of these genes, which encodes a secreted protein with an essential role in follicular development.

Case presentation: Our study investigates the cause of early secondary amenorrhea in 2 affected sisters with POI from a consanguineous Iranian family. Exome sequencing identified a novel homozygous GDF9 variant (c.275T $>$ C; p.Leu92Pro) in the probands. Based on family segregation analysis, the variant was detected in a heterozygous state in the parents of the affected sisters and their grandmother. Notably, neither the mother nor the grandmother showed symptoms of the disease. Bioinformatics analysis and protein structural alteration due to the substitution of leucine with proline also supported the deleterious potential impact of this variant.

Conclusion: In summary, our findings highlight the role of GDF9 biallelic variants in the etiology of POI and suggest a more cautious interpretation of heterozygous variants in the context of disease.