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MON-207 Identification of Monogenic Causes of Polycystic Ovary Syndrome by High Throughput Sequencing

Abstract BACKGROUND: Polycystic ovary syndrome (PCOS) is a common complex endocrine disorder, whose etiology remains to be elucidated. PCOS has a strong heritable component. Genome-wide association studies have identified several risk loci for PCOS; however, the identified candidate genes could explain less than 5% of PCOS heritability. This missing heritability might be explained by the presence of rare genetic variants with larger biological impact. High throughput sequencing (HTS) could be an interesting tool to identify these rare variants. OBJECTIVE: To identify rare genetic variants through HTS in a selection of patients with PCOS clinical relevant phenotypes or familial PCOS clusters. METHODS: Among a cohort of 130 PCOS patients, we selected 32 women presenting one or more of the following phenotypes: 1. adrenal hyperandrogenism (DHEA and/or DHEAS levels 1.5 higher the upper limit of the normal range); 2. primary amenorrhea; 3. severe insulin resistance (IR) (basal insulin >50 mUi/mL and/or after OGTT >300 mUI/mL); 4. normal androgen levels (total and free testosterone, androstenedione, DHEA and DHEAS in the normal range measured by gold standard methods). This group was studied through targeted gene sequencing panels (Miseq Illumina) including 50 genes involved in ovarian folliculogenesis, steroid hormone synthesis, gonadotropin action and insulin-signaling pathway, and genes suggested by monogenic/dygenic PCOS causes. Additional 2 families, with two PCOS sisters and their unaffected mother, were studied by exome sequencing (Hiseq Illumina). Allelic variants were considered pathogenic/potential pathogenic if they had a MAF<0.01 (Gnom AD and ExAC databases), were classified deleterious/probably deleterious by several prediction sites (i.e. SIFT, PolyPhen 2, Mutation Taster) and affect amino acids that are highly conserved among homologues (GERP scores). RESULTS: Among the 34 PCOS index patients studied, the phenotype was distributed as following: 15 with severe IR, 10 with adrenal hyperandrogenism, 2 normoandrogenic, 3 with primary amenorrhea and 4 familial cases. Twelve variants were identified in 10 patients (29.4%), affecting 6 genes: INSR, LMNA, POMC, GATA4, FSHR, H6PD, DLK1 and SCN1A. All genes were found once, except LMNA that was found in 4 different PCOS patients with severe IR. The variants in INSR, POMC and FSHR genes were found in the severe IR group, and in GATA4 in the adrenal hyperandrogenism group. The DLK1 and SCN1A variants were found in the two families studied through exome. CONCLUSION: High throughput sequencing allowed the identification of monogenic forms of PCOS, especially in patients with severe insulin resistance. The identification of rare genetic variants in PCOS patients might increase our comprehension of the pathogenesis of this disease, with positive clinical implications in patient’s treatment and genetic counseling.