Investigation of Copy Number Variations and Genetic Variants in POI

Condition(s) studied

Study 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.

Eligibility

Primary outcome measure(s)

• Identification of putative POI-related genes. — Year 1-20
  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
• Identification of genetic variants co-segregated with phenotype. — Year 1-20
  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.
• To combine array-CGH and WES data mining. — Year 1-20
  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).

Trial sites (1)

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