Premature Ovarian Failure (POF) Panel

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. To date, defects in at least 21 genes have been documented to cause POF (Layman. 2013. PubMed ID: 23499866; Bouilly et al. 2016. PubMed ID: 27603904). Pathogenic variants in genes involved in meiosis (HFM1, STAG3), in DNA repair (MCM8, MCM9), in genes encoding transcription factors (NR5A1, NOBOX, FIGLA, FOXL2 and SOHLH1), and in genes encoding TGF-ß signaling pathway (BPM15) have all been reported in POF (Bouilly et al. 2016. PubMed ID: 27603904; Patiño et al. 2017. PubMed ID: 28505269). Moreover, this panel contains a set of other genes associated with syndromes that may also present with POF, such as aromatase deficiency, blepharophimosis, ptosis and epicanthus inversus syndrome (BPES), Malouf syndrome, ovarian hyperstimulation syndrome, and Perrault syndrome. See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

This multi-gene panel analyzes genes associated with premature ovarian failure (POF). The detection rate of this NGS panel in a large cohort of female patients is unavailable in the literature, but pathogenic variants in 6 of the genes within this panel have been discovered in 13/100 (13%) of patients with POF (Bouilly et al. 2016. PubMed ID: 27603904).

Gross deletions or duplications have been reported in AIRE, CLPP, CYP17A1, CYP19A1, EIF2B2, FOXL2, GALT, LMNA and NR5A1 (Human Gene Mutation Database). Overall clinical sensitivity is difficult to predict due to the paucity of documented cases, but is expected to be low.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.3% coverage of all coding exons of the genes 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 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).

Genes without complete coverage: MCM8, NR5A1, and STAG3. A full list of regions not covered by NGS or Sanger sequencing is available upon request.

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).