Premature Ovarian Failure via the STAG3 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.

STAG3 encodes a meiosis-specific subunit of the cohesin ring, which ensures proper pairing and segregation of chromosomes during meiosis. Female mice devoid of Stag3 are sterile, and showed a lack of oocytes and ovarian follicles indicating a severe ovarian dysgenesis (Caburet et al. 2014. PubMed ID: 24597867). Autosomal recessive pathogenic variants, including nonsense and splicing variants as well as a small frameshift deletion and a frameshift duplication, in STAG3 have been reported to cause premature ovarian failure with primary amenorrhea (Caburet et al. 2014. PubMed ID: 24597867; Le Quesne Stabej et al. 2016. PubMed ID: 26059840; He et al. 2018. PubMed ID: 28393351; Bergant et al. 2018. PubMed ID: 28914264).

This test is predicted to detect pathogenic variants in ~1.5% of patients with premature ovarian failure (Patiño et al. 2017. PubMed ID: 28505269).

This test provides full coverage of all coding exons of the STAG3 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).