ESPE Abstracts

Introduction and aims: The current guidelines for the genetic workup of primary ovarian insufficiency (POI) include performing karyotype and assessing the Fragile X carrier state (FXS). We aimed to investigate the genetic etiologies of POI and assess the need for updated guidelines for POI workup.

Methods: We conducted a prospective trial that included individuals with non-iatrogenic, normal karyotype POI, referred to two endo-gynecologic fertility clinics. Demographic, clinical, laboratory, and imaging data were collected, and blood samples were drawn to extract DNA for FXS analysis and whole exome sequencing (WES), followed by extensive bioinformatics analysis.

Results: Thiry-nine individuals (15 adolescents) with a mean age of 24.4±8.7 years, were recruited. The mean age of menarche was 13.1±1.5 years, 28 experienced menstrual irregularities, whereas 11 had normal menses with infertility, and 12 had familial POI. We identified a genetic variation in 18 (46%) cases that might explain POI. Seven were classified as likely pathogenic or pathogenic and eleven cases were classified as a variant of unknown significance. Four other pathogenic variants were found in genes unrelated to POI (PKD2, PROKR2, BRCA2, DUOX2), but with further clinical implications. The genetic pathways distribution for POI included: 42% in DNA repair/meiosis/mitosis (STAG3, SYCE1, EXO1, FANCA, HSF2BP, ERCC6), 32% in ovarian/follicle growth (GDF9, FIGLA, RREB1, BMP8), 11% in metabolism & mitochondrial function (POR, PMM2), 11% in RNA metabolism (FMR1), and 5% in autophagy (ATG9B). We observed novel variants in known POI-causative genes (i.e. SYCE1, FANCA), variants in genes previously reported in isolated patients with POI (i.e. BMP8, EXO1), or only in an animal model (GREB1), and an autosomal dominant pattern of inheritance in families with POI in genes known to be a recessive pattern (i.e. FIGLA). We describe a unique oligogenic pattern among 3 families, with a combination of genes associated with POI (PMM2, ERCC6 & SMC1B, EXO1 & SIRT6, RREB1 & ATG9B). The results resulted in five fertility preservations among the individuals’ sisters, led to onco-genetic consultations for families with variants in DNA repair pathways linked to cancer susceptibility, and provided tailored counseling for both the patients and their families.

Conclusions: Identifying the genetic etiology of POI enables personalized medicine, improves care and fertility preservation for the index patient and her family, and contributes to the understanding of the molecular basis of POI. We assert that WES should be integrated into the guidelines in the POI workup.