none 10.18502/ijrm.v23i12.20718 Knowledge E DMCC Knowledge E DMCC 7770 190172278 313405 20260214174527000 10.18502 2026-02-14T14:02:55Z 2026-02-14T13:45:28Z 0 International Journal of Reproductive BioMedicine (IJRM) IJRM 2476-3772 2476-4108 02 14 2026 23 12 Behzad Haj Mohammad Hassani Niloofar Ghasemi Kianoosh Malekzadeh 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. 02 14 2026 1 https://doi.org/10.18502/knecrossmarkpolicy knepublishing.com true https://creativecommons.org/licenses/by-nc/4.0 10.18502/ijrm.v23i12.20718 https://knepublishing.com/index.php/ijrm/article/view/20718 https://knepublishing.com/index.php/ijrm/article/download/20718/31486 https://knepublishing.com/index.php/ijrm/article/download/20718/31486 http://ijrm.ir/article-1-3709-en.html 10.1007/s10815-021-02144-x [1] Verma KP, Thompson B, Wolfe J, Price S, Djukiadmodjo F, Trainer A. A homozygous truncating variant in GDF9 in siblings with primary ovarian insufficiency. J Assist Reprod Genet 2021; 38: 1539–1543. 10.1093/humrep/dew027 [2] Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, et al. ESHRE guideline: Management of women with premature ovarian insufficiency. Hum Reprod 2016; 31: 926–937. 10.34172/iejm.2020.15 [3] Moraghebi M, Rafat M, Mousavi P, Malekzadeh K. Manifestly altered microRNAs in poly cystic ovary syndrome. Int Electronic J Med 2020; 9: 86–91. 10.1007/s11033-025-10907-3 [4] Hassani BHM, Ghasemi N, Malekzadeh K. Novel compound heterozygous NDNF variants in congenital hypogonadotropic hypogonadism: Insights into genotype-phenotype correlation and infertility. Mol Biol Rep 2025; 52: 818. 10.1210/er.2016-1047 [5] Tucker EJ, Grover SR, Bachelot A, Touraine P, Sinclair AH. Premature ovarian insufficiency: New perspectives on genetic cause and phenotypic spectrum. Endocr Rev 2016; 37: 609–635. 10.1007/s10815-018-1232-3 [6] Juárez-Rendón KJ, García-Ortiz JE. Evaluation of four genes associated with primary ovarian insufficiency in a cohort of Mexican women. J Assist Reprod Genet 2018; 35: 1483–1488. 10.1056/NEJMcp2116488 [7] Stuenkel CA, Gompel A. Primary ovarian insufficiency. N Engl J Med 2023; 388: 154–163. 10.1016/j.gene.2024.148734 [8] Jordan P, Verebi C, Hervé B, Perol S, Bernard V, Karila D, et al. Revisiting GDF9 variants in primary ovarian insufficiency: A shift from dominant to recessive pathogenicity? Gene 2024; 927: 148734. 10.1111/cge.13156 [9] França MM, Funari MFA, Nishi MY, Narcizo AM, Domenice S, Costa EMF, et al. Identification of the first homozygous 1-bp deletion in GDF9 gene leading to primary ovarian insufficiency by using targeted massively parallel sequencing. Clin Genet 2018; 93: 408–411. 10.3390/biomedicines12040785 [10] Almatrafi AM, Hibshi AM, Basit S. Exome sequencing to identify novel variants associated with secondary amenorrhea and premature ovarian insufficiency (POI) in Saudi women. Biomedicines 2024; 12: 785. 10.1007/s10815-018-1349-4 [11] Yang X, Touraine P, Desai S, Humphreys G, Jiang H, Yatsenko A, et al. Gene variants identified by whole-exome sequencing in 33 French women with premature ovarian insufficiency. J Assist Reprod Genet 2019; 36: 39–45.