Investigation of Copy Number Variations and Genetic Variants in POI

NCT05327283 | Recruiting

• 1 other identifier: POI genome
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

Primary Ovarian Insufficiency

Keywords

Premature ovarian failure; array-CGH; NGS

Outcome Measures

Primary Outcomes (3)

• Identification of putative POI-related genes.

  Genomic imbalances (\<5 Mb in size: copy number variations (CNVs) as micro-deletions and micro-duplications) will be detected in sporadic idiopathic POI patients with the purpose to clarify the role of CNVs in POI pathogenesis and to better unveil both novel candidate genes and pathogenic mechanisms

  Year 1-20

• Identification of genetic variants co-segregated with phenotype.

  Novel genetic variants not previously anticipated will be found: given the variants co-segregate with phenotype, whole-exome sequencing approach in consanguineous and POI pedigrees will identify the causative gene and variants that cause the phenotype.

  Year 1-20

• To combine array-CGH and WES data mining.

  The cumulative effect of different genes/variants will be considered in support of the polygenicity of POI and its heterogeneous phenotype (primarily, the sporadic and familial ones).

  Year 1-20

Study Arms (2)

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).

Familial POI

Familial POI cases and not-affected members of pedigrees.

Eligibility Criteria

• Age: 15 Years - 38 Years
• Sex: female
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Idiopathic, sporadic and familial POI cases.

You may qualify if:

• 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).

You may not qualify if:

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

Sponsors & Collaborators

• Ospedale Policlinico San Martino: lead

Study Sites (1)

UOS Fisiopatologia della Riuproduzione Umana

Genova, Italy

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

peripheral blood samples

MeSH Terms

Conditions

Primary Ovarian Insufficiency

Condition Hierarchy (Ancestors)

Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases

Study Officials

• Paola Scaruffi

  Ospedale San Martino

  PRINCIPAL INVESTIGATOR

• Paola Anserini

  Ospedale San Martino

  STUDY DIRECTOR

Central Study Contacts

Paola Scaruffi, PhD

CONTACT

paola.scaruffi@hsanmartino.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: March 17, 2022
• First Posted: April 14, 2022
• Study Start: January 31, 2012
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030
• Last Updated: April 25, 2022

Record last verified: 2022-04

Locations

IT (1)