Monogenic causes of premature ovarian insufficiency in adolescence

Premature ovarian insufficiency (POI) is a condition characterized by hypergonadotropic hypogonadism and amenorrhea, which rarely manifests in adolescence. Up to 50% of POI cases are idiopathic. We conducted molecular diagnostic testing of 39 patients who experienced the onset of POI before the age of 18, all of whom had a normal female karyotype. This involved FMR1 CGG repeats testing and whole-exome sequencing. None of the patients were found to have a premutation in the FMR1 gene. In 17 out of 39 patients (43.5%), variants were identified across 12 genes. A diagnosis of monogenic POI was established in 7 patients (18%) based on the detection of pathogenic and likely pathogenic variants. Syndromic forms of POI were observed in 3 cases (8%), while isolated POI was noted in 4 cases (10%). In 4 patients (10%), variants of uncertain clinical significance were found in the STAG3, LMNA, SPIDR, and NOBOX genes. Additionally, 6 patients (15.5%) had heterozygous variants on one allele in genes associated with autosomal recessive POI. We recommend that patients with onset of POI in adolescence undergo genetic counseling and molecular genetic testing.

1. Panay N., Anderson R.A., Bennie A., et al. Evidence-based guideline: premature ovarian insufficiency. Human Reproduction Open. 2024; 2024(4): hoae065, https://doi.org/10.1093/hropen/hoae065

2. Gruber N., Kugler S., de Vries L., et al. Primary Ovarian Insufficiency Nationwide Incidence Rate and Etiology Among Israeli Adolescents. J Adolesc Health. 2020;66(5):603-609. doi: 10.1016/j.jadohealth.2019.11.315.

3. Long P., Wang L., Tan H., et al. Oligogenic basis of premature ovarian insufficiency: an observational study. J Ovarian Res. 2024;17(1):32. doi: 10.1186/s13048-024-01351-1.

4. Chen Z., Chen H., Yuan K., Wang C. A 15q25.2 microdeletion phenotype for premature ovarian failure in a Chinese girl: a case report and review of literature. BMC Med Genomics. 2020;13(1):126. doi: 10.1186/s12920-020-00787-w.

5. Meng T., Zhang W., Zhang R., et al. Ovarian Reserve and ART Outcomes in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Patients With FOXL2 Mutations. Front Endocrinol (Lausanne). 2022;13:829153. doi: 10.3389/fendo.2022.829153.

6. Tucker E.J., Jaillard S., Grover S.R., et al. TP63-truncating variants cause isolated premature ovarian insufficiency. Hum Mutat. 2019;40(7):886-892. doi: 10.1002/humu.23744.

7. Tsabai P.N., Pavlova N.S., Shatylko T.V., et al. Novel STAG3 variant causes oligoasthenoteratozoospermia with high sperm aneuploidy rate. J Assist Reprod Genet. 2025;42(4):1239-1245. doi: 10.1007/s10815-025-03417-5.

8. De Caro J.J., Dominguez C., Sherman S.L. Reproductive health of adolescent girls who carry the FMR1 premutation: expected phenotype based on current knowledge of fragile X-associated primary ovarian insufficiency. Ann N Y Acad Sci. 2008;1135:99-111. doi: 10.1196/annals.1429.029.