Molecular analysis of Candidates Genes for Polycystic Ovary Syndrome Through New Generation Sequencing

Abstract

Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorders affecting 7-15% of women in the reproductive age. PCOS clinical symptoms include hirsutism, infertility, menstrual dysfunction, obesity, metabolic syndrome and increased cardiovascular risk. The definitive etiology remains to be elucidated, but PCOS has a strong heritable component based on familial clustering and twin studies. Genome Wide Association Studies (GWAS) have emerged as an important tool for complex disease investigation and have identified several new risk loci revealing candidate genes for PCOS. Despite these findings, the candidate genes have explained less than 5% of heritability. The low heredity rate could be explained by the presence of rare genetic variants with larger biological impact. The objectives of this research project are:1- to identify rare pathogenic sequence variants involved in PCOS pathogenesis through targeted gene sequencing panel designed based on the GWAS findings, genes known to be involved in ovarian folliculogenesis, steroid hormone synthesis, gonadotropin action and insulin-signaling pathway, and genes suggested by monogenic diseases and/or animal models; 2- to identify new candidate genes using global exome sequencing in selected group of patients;Cohort and methods: to enhance the project power we investigate the presence of pathogenic variants in a specific PCOS group: a) familial PCOS patients, b) PCOS associated with adrenal hyperandrogenemia, c) PCOS patients with primary amenorrhea, d) PCOS patients with severe insulin resistance, e) PCOS patients with associated syndromic phenotype. Mutational analysis of candidate genes will be performed through massively parallel sequencing. This research will potentially allow the identification of new molecular mechanisms involved in PCOS pathogenesis, leading, in the long term, the development of individualized care of patients and families. (AU)