Premature Ovarian Failure via the MCM9 Gene

Premature Ovarian Failure (POF), also known as primary ovarian insufficiency, 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. POF is a major cause of infertility and affects 1% of women before the age of 40. 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 disorders, 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. MCM9 is a newly discovered gene causative for ovarian dysgenesis. Minichromosomal maintenance complex component 9 (MCM9) is a member of evolutionarily conserved MCMs protein family of eight proteins (MCM2-9). Studies of MCM9 have demonstrated it is responsible for homologous recombination mediated DNA repair during gametogenesis (Lutzmann et al 2012. PubMed ID: 22771120). Recently, autosomal recessive pathogenic variants, including nonsense and splicing variants as well as a small frameshift indel, in MCM9 have been reported to cause POF and genomic instability (Wood-Trageser et al. 2014. PubMed ID: 25480036; Desai et al. 2016. PubMed ID: 27802094; Fauchereau. 2016. PubMed ID: 26771056).

This test is predicted to detect pathogenic variants in 5% of patients with premature ovarian failure (Desai et al. 2016. PubMed ID: 27802094).

This test provides full coverage of all coding exons of the MCM9 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).