Endocrine Abstracts

Primary ovarian insufficiency (POI) affects 1% of women before age 40 years, and in 70-90% of cases is defined as idiopathic. Although numerous POI-associated genes have been identified in recent years, the prevalence and pathogenicity of individual rare gene variants is still difficult to establish. The aim of our study was to retrospectively analyze the correlation between genotype and phenotype in patients with idiopathic POI, providing a more detailed characterization of POI-associated gene variants. 83 patients were enrolled, clinical data at diagnosis were collected and genetic analysis was performed with NGS technique to search for rare variants (RVs) in 9 candidate genes (BMP15, FIGLA, FOXL2, GDF9, NOBOX, NR5A1, FSHR, SYCE1, STAG3). We also classified the RVs we found according with ACMG criteria. Thus, RVs "of uncertain significance," "probably pathogenic," and "pathogenic" were defined as "potentially pathogenic variants" (PPRVs). Family history of POI was present in 27.5% of patients with secondary amenorrhea (SA) and 6.7% of patients with primary amenorrhea (PA). Patients with PA presented phenotypic abnormalities associated with ovarian failure in 25% percent of cases, while those with of SA in 8.7% of cases. However, none of these differences were found to be statistically significant. Genetic analysis showed the presence of several RVs and PPRVs in the 9 genes analyzed, with STAG3 being the gene with the highest enrichment in rare variants in our sample. In patients with PA we observed a greater enrichment, statistically significant, in RVs (respectively 43.5% in PA vs in 13.7% SA) and PPRVs, as well as in biallelic and oligogenic RVs (respectively 8.7% and 13% in PA vs 0% and 2% in SA). In addition, we found the presence of family history in 40% of PPRV carrier patients (vs 20% in PPRV-negative cases). Finally, no difference in prevalence of associated phenotypes was found in patients carrying RVs or not. Our analysis showed that higher enrichment in RVs, especially those with likely pathogenetic impact, correlates with greater clinical severity. In particular, the presence of oligogenicity and homozygosity/ compound heterozygosity appears to correlate with PA. In contrast, the more blunted clinical forms, presenting with SA, seem to associate less frequently with RVs in candidate genes, while showing even more prevalent family history: genetic background may consist of a combination of polymorphic variants or rare variants in genes not classically associated with POI, combined with the effect of stochastic and environmental factors.