Identification of rare CNVs involving genes acting in oocyte maturation and differentiation in a cohort of patients affected by Primary Ovarian Insufficiency

with an incidence of 1:10,000 women by age 20, 1:1,000 by age 30, 1:100 by age 40. Despite the identification of numerous candidate genes in POI women, the genetic origin has been clarified only in about 20% of the patients. The patients showing the most severe phenotype, characterized by the absence of pubertal development and primary amenorrhea (PA) and 46,XX ovarian dysgenesis, are indeed rare but the search for genetic variations in this extreme phenotype may be more effective in identifying novel pathogenic mechanisms. To unveil new POI causative genes we searched for rare high-penetrance CNVs involving genes essential for ovarian function in a cohort of 46,XX patients affected by PA. Forty-three patients were processed by high resolution array-CGH. Thirty-seven patients were found to bear 98 CNVs not reported to date in healthy subjects according to the Database of Genomic Variants (DGV), and 11 CNVs already reported in DGV but relevant to gene content, for a total of 109 CNVs. Several of these genomic alterations include genes implicated in: meiotic resumption, oogonia maintenance, first-polar-body extrusion, DNA repair, follicle adhesion/migration regulation, actin remodelling, cholesterol endocytosis, Ca2+ homeostasis. Once characterized by other molecular and bioinformatics approaches, the results of this study are promising to expand the knowledge about the molecular pathways involved in POI pathogenesis and probably provide the basis for a more accurate genetic diagnosis of POI patients.