Investigation of Copy Number Variations and Genetic Variants in POI

NCT ID: NCT05327283

Last Updated: 2022-04-25

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 100 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2012-01-31
• Study Completion Date: 2030-12-31

Brief Summary

Primary ovarian insufficiency (POI), also known as premature ovarian failure, is an ovarian defect characterized by the premature (before the age of 40 years) depletion of ovarian follicles. POI affects about 1% of women, reaching 30% in some familial cases.

This heterogeneous disorder is characterized by progressive cessation of the ovarian function with temporary or intermittent amenorrhea associated with elevated serum FSH concentration and low AMH dosage. Low serum AMH dosage is able to detect a diminished ovarian pool occurring before the onset of FSH elevation and the ultimate deficiency leading to amenorrhea.

POI causes infertility and a poor ovarian response in IVF stimulations, and it has important health consequences for affected patients, including psychological distress, infertility, osteoporosis, autoimmune disorders, ischaemic heart disease.

Although the cause of POI remains unknown in about 80% of the cases, several mechanisms have been proposed to explain ovarian dysfunction. Currently, a wide spectrum of causes has been linked to POI, including genetic, autoimmune, infectious, or iatrogenic ones.

Genetic causes are highly heterogeneous and might explain at least some of the sporadic idiopathic cases, which comprise 50-90% of cases. Ten to fifteen percent of cases are X-linked abnormalities, mainly Turner Syndrome (45,X) or X structural abnormalities such as X deletions, X inversions, isochromosomes or X-autosome translocations. Also fragile X mental retardation 1 (FMR1) gene permutation (defined as having 55 to 200 CGG repeats in the 5' untranslated region of the gene) is another frequent genetic etiology.

Irrespectively, the majority of cases remains idiopathic, and identifying precise causative genes for POI has been challenging.

Detailed Description

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.

Conditions

Primary Ovarian Insufficiency

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Sporadic POI

Idiopathic, sporadic POI Caucasian cases. The inclusion criteria will be:

• 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).

No interventions assigned to this group

Familial POI

Familial POI cases and not-affected members of pedigrees.

No interventions assigned to this group

Eligibility Criteria

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.

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 38 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Ospedale Policlinico San Martino

OTHER

Sponsor Role: lead

Responsible Party

Scaruffi

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Paola Scaruffi

Role: PRINCIPAL_INVESTIGATOR

Ospedale San Martino

Paola Anserini

Role: STUDY_DIRECTOR

Ospedale San Martino

Locations

UOS Fisiopatologia della Riuproduzione Umana

Genova, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Paola Scaruffi, PhD

Role: CONTACT

paola.scaruffi@hsanmartino.it

Facility Contacts

Paola Scaruffi, PhD

Role: primary

paola.scaruffi@hsanmartino.it

Other Identifiers

POI genome

Identifier Type: -

Identifier Source: org_study_id