Ovarian Dysgenesis and Ovarian Hyperstimulation Syndrome via the FSHR Gene

Ovarian Dysgenesis 1 (ODG1), also called XX Gonadal Dysgenesis (XX GD), is an autosomal recessive disease caused by pathogenic variants in the Follicle-Stimulating Hormone Receptor gene (FSHR) (Aittomaki et al. 1995. PubMed ID: 7553856). The classical features of ODG1 are poorly developed streak ovaries and primary amenorrhea in conjunction with a normal 46,XX karyotype (Aittomaki, 1994. PubMed ID: 8178824). However, pathogenic variants in FSHR can also cause secondary amenorrhea in the absence of any apparent pubertal defects (Touraine et al. 1999. PubMed ID: 10551778) and varying degrees of oligozoospermia or teratozoospermia in men (Tapanainen et al. 1997. PubMed ID: 9020851). All patients with FSHR pathogenic variants, both men and women, exhibit elevated circulating levels of follicle-stimulating hormone (FSH).

Although inactiving pathogenic variants in FSHR result in ODG1, activating pathogenic variants cause Ovarian Hyperstimulation Syndrome (OHSS). More than one million couples worldwide seek reproductive assistance each year because of infertility (Chandra et al. 2005. PubMed ID: 16532609; Nyboe Andersen et al. 2009. PubMed ID: 19225009). In at least 75% of the cases, ovarian stimulation, to induce the development of multiple dominant follicles and maturation of many oocytes, is an integral part of the treatment regimen. Typically, ovarian stimulation is achieved by administering exogenous human Menopausal Gonadotropin (hMG), a natural mixture of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotropin (hCG) (Macklon et al. 2006. PubMed ID: 16434510). OHSS is an iatrogenic complication due to the exogenous administration of hMG and affects upwards of 5% of all women undergoing treatment for infertility (Delvigne and Rozenberg. 2002. PubMed ID: 12498425; Abramov et al. 1999. PubMed ID: 10469676). In addition, OHSS can spontaneously occur in women during the third month of an otherwise normal pregnancy. In these cases, increased endogenous levels of hCG from the ongoing pregnancy is thought to be the cause (Elchalal and Schenker. 1997. PubMed ID: 9221989). The primary symptoms of OHSS are abdominal discomfort, nausea, vomiting and diarrhea due to enlarged polycystic ovaries. In the most severe instances, rupture and hemorrhaging of ovarian cysts, organ failure and death can occur (Delvigne and Rozenberg. 2003. PubMed ID: 12638783).

To date, over thirty pathogenic variants have been described for the Follicle-Stimulating Hormone Receptor (FSHR) gene (Human Gene Mutation Database). Homozygous or compound heterozygous strong inactivating pathogenic variants, such as p.Ala189Val, p.Pro587His or a deletion of exons 9-10 cause Ovarian Dysgenesis, characterized by symptoms of primary amenorrhea, delayed or incomplete pubertal development, and small immature ovaries (Aittomaki et al. 1995. PubMed ID: 7553856; Kuechler et al. 2010. PubMed ID: 20087398). By contrast, weaker pathogenic variants, such as p.Arg573Cys or p.Leu601Val, exhibit some residual (5-25%) receptor activity and much milder symptoms, primary or secondary amenorrhea with apparently normal pubertal development (Touraine et al. 1999. PubMed ID: 10551778). Due to a likely founder effect, the p.Ala189Val pathogenic variant has a relatively high frequency (~1%) in the Finnish population, but is very rare in all other tested populations (Jiang et al. 1998. PubMed ID: 9851774). The frequencies of other FSHR pathogenic variants have not been reported. Pathogenic variants in FSHR are the most common cause of recessively inherited Ovarian Dysgenesis.

Men homozygous for the strong inactivating pathogenic variant p.Ala189Val are healthy and normally masculinized, but have low testicular volume and abnormal sperm parameters (Tapanainen et al. 1997. PubMed ID: 9020851). Currently, no other FSHR pathogenic variants have been described in males.

OHSS can be caused by dominant pathogenic variants in the Follicle Stimulating Hormone Receptor gene (FSHR). Normally, the FSHR protein is exclusively activated by FSH. However, changes at a few amino acids (Ser128, Thr449, Ile545, and Asp567) of FSHR decrease its specificity for FSH and increase its sensitivity to other hormones, such as LH and hCG (De Leener et al. 2008. PubMed ID: 17721928; De Leener et al. 2006. PubMed ID: 16278261; Smits et al. 2003. PubMed ID: 12930928; Vasseur et al. 2003. PubMed ID: 12930927). Thus, patients who have a heterozygous pathogenic variant of one of these amino acids are likely to develop OHSS during the course of treatment for infertility, particularly if hMG is used to stimulate ovulation.

In Finland, forty percent of women with amenorrhea are predicted to have a pathogenic variant in the FSHR gene (Reindollar and McDonough. 1984. PubMed ID: 6379174; Aittomaki. 1994. PubMed ID: 8178824).

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