Investigation of Copy Number Variations and Genetic Variants in POI

Although in the last decades an increasing number of aberrant genes involved in POI were identified, currently only a minority of affected women can be explained at gene level. Elucidating the biology of the premature declining ovarian function is paramount to develop better testing and treatment strategies for affected women in the future.

Importantly, two clinical features remain unexplained: i) the overall sporadic nature of POI, and ii) observations of patients harboring the identical mutation yet developing POI either early in life (puberty) or later (< 40 years old). Therefore, the investigators postulate that defects affecting more than one gene might explain this variability. Based on investigators' preliminary data and literature reports, it is likely that a synergistic effect of several variant/gene abnormalities may underlie the idiopathic POI phenotype.

The investigators hypothesize that different genome-wide strategies (namely, high resolution array-CGH and WES) may discover genetic variants without the limitation of a single candidate or a panel of candidates, and thus are more promising for explanation of the genetic heterogeneity of POI and elucidating the pathogenic mechanisms.

Inclusion criteria

• age at diagnosis <38 years;
• a normal 46,XX karyotype (no FRM1 premutation);
• at least one marker of ovarian reserve not age-appropriate:

• baseline FSH levels > cut-off [1] and/or
• age-specific AMH < cut-off [2] and/or
• AFC < 5; and/or
• cancellation of a PMA cycle because of poor response (<3 follicles) to high-dose gonadotrophins (250 U/die) and/or
• retrieval of < 4 oocytes in response to high-dose stimulation protocols (3000 U of gonadotrophins).

Exclusion criteria

• patients with POI-related conditions, such as ovarian surgery or previous chemo- or radio-therapy; endometriosis or known autoimmune or metabolic diseases.