Genetics Investigation of Idiopathic Premature Ovarian Insufficiency: Contribution of Array-CGH and Next-Generation Sequencing

<b>Objective(s):</b> Premature ovarian insufficiency (POI), affecting 1% of women, is characterized by the loss of ovarian activity with amenorrhea or oligomenorrhea and increased gonadotropins occurring before the age of 40 years. Iatrogenic, autoimmune, and genetic causes are known to be involved in POI, but nearly 70% of all forms remain unexplained. Recent and new genetic analyses promote the identification of new candidate genes. The aim of this study was to evaluate the contribution of array-CGH and next-generation sequencing (NGS) in the diagnosis of POI. <b>Study design:</b> Twenty-eight idiopathic POI patients with primary or secondary amenorrhea underwent genetic screening by array-CGH and NGS using a custom capture design of 163 genes known or suspected to be involved in ovarian function. The clinical, biological, and ultrasound characteristics of the patients were also recorded. <b>Results:</b> Four of the twenty-eight patients had primary amenorrhea (14.3%), and twenty-four (85.7%) had secondary amenorrhea, with an average age at diagnosis of 27.7. Eleven patients (39.3%) had a family history of POI. Our study identified a genetic anomaly in 16 of 28 patients (57.1%): one patient carried a causal copy number variation (CNV), eight patients carried a causal single nucleotide variation (SNV)/indel variation (28.6%), and seven other patients carried variants of uncertain significance. <b>Conclusions:</b> Our study was the first to combine genetic analyses by using both array-CGH and NGS in the same patients. It confirmed the usefulness of both analyses in the identification of pathogenic variations responsible for idiopathic POI. Early genetic diagnosis plays a major role in the management of complications and the screening of relatives.