Premature Ovarian Failure via the PSMC3IP Gene

Premature Ovarian Failure (POF), also known as primary ovarian insufficiency (POI), is a genetically and phenotypically heterogeneous disorder characterized by primary amenorrhea or loss of menstrual function before the age of 40. Patients with POF often have elevated levels of follicle-stimulating hormone (FSH) and decreased levels of estrogen (Nelson. 2009. PubMed ID: 19196677). POF, in the most severe form, is a result of ovarian dysgenesis in which pubertal development is also severely affected. Approximately 50% of patients have varying and unpredictable ovarian function, and 5 to 10% of patients with POF may conceive without treatment (Nelson. 2009. PubMed ID: 19196677). There are several causes of premature ovarian failure, including chromosomal abnormalities, pathogenic sequence variants, autoimmune disorder, and environmental factors. POF can be isolated or part of a genetic syndrome (Kovanci and Schutt. 2015. PubMed ID: 25681846).

Approximately 10-30% of POF cases have familial inheritance (Vegetti et al. 1998. PubMed ID: 9740426; van Kasteren et al. 1999. PubMed ID: 10527968). The inheritance can be autosomal recessive, dominant or X-linked. Proteasome 26S subunit, ATPase, 3-Interacting Protein (PSMC3IP) is a nuclear, tissue-specific protein with multiple functions. It is critical for meiotic recombination and acts as a coactivator of ligand dependent transcription mediated by nuclear receptors, including the estrogen receptors (ER) and the androgen receptor. A homozygous 3-bp deletion in the PSMC3IP gene has been reported to be pathogenic in a large consanguineous Arab Palestinian pedigree with hypergonadotropic ovarian dysgenesis (Zangen et al. 2011. PubMed ID: 21963259). A homozygous nonsense variant in the PSMC3IP gene has also been reported to be pathogenic in patients with primary ovarian insufficiency (Al-Agha et al. 2018. PubMed ID: 29240891).

This test is predicted to detect pathogenic variants in ~1% of patients with premature ovarian failure (Al-Agha et al. 2018. PubMed ID: 29240891).

This test provides full coverage of all coding exons of the PSMC3IP gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).