SUN-147 Clinical And Genetic Assessment Of Women With Polycystic Ovary Syndrome And Early-onset Sexual Development

Abstract Disclosure: I.F. Machado: None. F.R. Tinano: None. A.P. Canton: None. L.G. Gomes: None. Introduction: Polycystic ovary syndrome (PCOS) and central precocious puberty (CPP) are reproductive conditions with potentially shared pathophysiological and genetic mechanisms, both associated with adverse metabolic outcomes. These conditions involve neuroendocrine dysregulation—such as increased GnRH and LH pulsatility—and are influenced by factors related to energy balance. Although the association between early sexual development (ESD) and PCOS remains controversial in epidemiological studies, emerging genetic evidence—such as a DLK1 variant in the Notch signaling pathway—reinforces the possibility of a shared genetic background. Objectives: (1) To characterize clinical, hormonal, and metabolic differences between patients with PCOS and ESD and those with isolated PCOS; (2) To identify novel candidate genes associated with the PCOS-ESD overlap through whole-exome sequencing (WES). Methods: Clinical, biochemical, and hormonal data from 230 women with PCOS were evaluated, comparing 34 women with PCOS and ESD to 196 with normal pubertal development. PCOS diagnosis followed the Rotterdam criteria. ESD was defined by the presence of thelarche before age 8 associated with advanced bone age and pubertal levels of luteinizing hormone (LH), or by self-reported menarche before age 10, an indirect marker of undiagnosed CPP. WES was performed in 18 patients with PCOS and ESD. Genetic variants were prioritized based on functional impact, low population frequency (MAF < 0.1%), and in silico predictions. Results: No significant clinical, hormonal, or metabolic differences were observed between patients with PCOS and ESD and those with normal pubertal development. Six genetic variants of interest were identified among patients with the PCOS-ESD association. A notable high-impact frameshift variant was detected in the last exon of NOTCH2, a gene highly expressed in ovarian tissue, likely leading to Notch pathway activation. Additional variants were identified in genes associated with metabolic alterations, including a frameshift in GCKR, a stop-gain in TNNI3K, and deleterious missense variants in ABCC8, ADCY5, and TSC2. The TSC2 variant was found in a patient with early-onset breast cancer. Conclusion: Women with PCOS and early sexual development did not show worse metabolic or reproductive outcomes compared to those with normal pubertal development. Six genetic variants with biological plausibility for contributing to the PCOS-ESD intersection were identified, all related to metabolic pathways. The most impactful variant involves the Notch signaling pathway, suggesting a potential role in regulating both reproductive and metabolic processes. These findings offer new insights into mechanisms underlying reproductive dysfunction. Presentation: Sunday, July 13, 2025