Premature Ovarian Failure via the FIGLA Gene

Premature Ovarian Failure (POF), also known as premature 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. 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. To date, defects in at least 15 genes, including FIGLA, have been reported to cause POF (Layman. 2013. PubMed ID: 23499866). FIGLA is a germ cell-specific basic helix-loop-helix (bHLH) transcription factor that regulates expression of oocyte-specific genes. It is critical in oocyte differentiation and required for normal folliculogenesis (Huntriss et al. 2002. PubMed ID: 12468641). Studies of FIGLA have demonstrated that pathogenic variants disrupted FIGLA binding to its heterodimer bHLH transcription factor TCF3 and potentially the formation of primordial follicles (Zhao et al. 2008. PubMed ID: 18499083; Bouilly et al. 2016. PubMed ID: 27603904). Heterozygous pathogenic variants, including missense variants and small deletions (one inframe and one frame-shift), in FIGLA have been reported to cause POF (Zhao et al. 2008. PubMed ID: 18499083; Bouilly et al. 2016. PubMed ID: 27603904).

To date, only a few pathogenic variants in FIGLA have been documented. In a cohort of 100 Chinese patients with Premature Ovarian Failure, three pathogenic variants in FIGLA were identified (Zhao et al. 2008. PubMed ID: 18499083).

No large deletions or duplications involving FIGLA have been reported (Human Gene Mutation Database).

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