Investigation of Copy Number Variations and Genetic Variants in POI
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- This is an observational study: the protocol does not assign a study treatment.
- Who it may be relevant to
- Registry conditions: Primary Ovarian Insufficiency. Basic parameters: 15 years — 38 years · Female.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Italy
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Official title
Insight Into the Genomics of Idiopathic Premature Ovarian Insufficiency
Overview
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.
Primary outcome measures
- Identification of putative POI-related genes. [Time frame: Year 1-20]
- Identification of genetic variants co-segregated with phenotype. [Time frame: Year 1-20]
- To combine array-CGH and WES data mining. [Time frame: Year 1-20]
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.
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Study design
- Observational model
- Cohort
Study locations
Italy · 1 center
- UOS Fisiopatologia della Riuproduzione Umana — Genova
Identifiers
NCT: NCT05327283 · POI genome