Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSPCRESPO, Raiane P.ROCHA, Thais P.MONTENEGRO, Luciana R.NISHI, Mirian Y.JORGE, Alexander A. L.MACIEL, Gustavo A. R.BARACAT, EdmundLATRONICO, Ana ClaudiaMENDONCA, Berenice B.GOMES, Larissa G.2022-08-122022-08-122022JOURNAL OF THE ENDOCRINE SOCIETY, v.6, n.9, 2022https://observatorio.fm.usp.br/handle/OPI/48268Context: Polycystic ovary syndrome (PCOS) etiology remains to be elucidated, but familial clustering and twin studies have shown a strong heritable component. Objective: The purpose of this study was to identify rare genetic variants that are associated with the etiology of PCOS in a preselected cohort. Methods: This prospective study was conducted among a selected group of women with PCOS. The study's inclusion criteria were patients with PCOS diagnosed by the Rotterdam criteria with the following phenotypes: severe insulin resistance (IR), normoandrogenic-normometabolic phenotype, adrenal hyperandrogenism, primary amenorrhea, and familial PCOS. Forty-five patients were studied by target sequencing, while 8 familial cases were studied by whole exome sequencing. Results: Patients were grouped according to the inclusion criteria with the following distribution: 22 (41.5%) with severe IR, 13 (24.5%) with adrenal hyperandrogenism, 7 (13.2%) with normoandrogenic phenotype, 3 (5.7%) with primary amenorrhea, and 8 (15.1%) familial cases. DNA sequencing analysis identified 1 pathogenic variant in LMNA, 3 likely pathogenic variants in INSR, PIK3R1, and DLK1, and 6 variants of uncertain significance level with interesting biologic rationale in 5 genes (LMNA, GATA4, NR5A1, BMP15, and FSHR). LMNA was the most prevalent affected gene in this cohort (3 variants). Conclusion: Several rare variants in genes related to IR were identified in women with PCOS. Although IR is a common feature of PCOS, patients with extreme or atypical phenotype should be carefully evaluated to rule out monogenic conditions.engopenAccesspolycystic ovary syndromegeneticsinsulin resistancetarget sequencingexome sequencinggenome-wide associationmutationsvariantsgeneheritabilityprevalenceresistancereceptorroleswomenarticleCopyright ENDOCRINE SOC10.1210/jendso/bvac106Endocrinology & Metabolism2472-1972