SCIENTIFIC BACKGROUND

FMR1

With up to 40%, ovarian disorders are among the most important infertility factors in women. Premature ovarian insufficiency (POI) manifests itself as secondary amenorrhea and occurs in about 1% of all women before the age of 40. The cause is a disturbance in the hypothalamic-pituitary-ovarian regulatory circuit. Biochemically, it is characterized by hypergonadotropic hypogonadism. This constellation results in climacteric symptoms (climacterium praecox) and, in some cases, other neurological, metabolic, and cardiovascular symptoms in addition to infertility.

 

The causes are as follows:

 

  • Genetic factors: implicated in about 20-25% of cases
  • Autoimmune reactions: causing approximately 10-15% of cases
  • Iatrogenic causes: responsible for 30-40% of cases
  • Idiopathic reasons: accounting for 40-60% of cases

 

Different genes on the X chromosome contribute to ovarian function. POI occurs, for example, in 4-5% of women with Ullrich-Turner syndrome who did not have primary amenorrhea and in partial X monosomies.

 

Premutations (CGG repeat of 55-200 repeats) in the FMR1 gene are currently the most common cause of premature ovarian failure, accounting for 10-15%. Approximately 20% of all premutation carriers develop POI. In women with sporadic POI, premutations are found in 0.8-7.5% of cases. In women with familial POI, the frequency of a premutation is up to 13%. Genetic counseling is indicated in those of childbearing potential, as there is both an increased risk of having children with fragile X syndrome and a risk of onset of menopause before the childbearing potential is realized.

 

In another candidate gene, BMP15 (Human Bone Morphogenetic Protein-15, region Xp11.2), a relevant pathogenic variant was detected in 2% of women with POI. The gene contains two exons and encodes an oocyte-specific growth and differentiation factor that stimulates follicle genesis and granulosa cell growth.

 

Pathogenic variants in the follicle-stimulating hormone receptor (FSHR) gene have been detected in patients with premature ovarian failure. This gene is located on chromosome 2p21-p16 and consists of 10 exons. The intact receptor is a prerequisite for normal gonadal development, germ cell production and sexual maturation at puberty.

 

Furthermore, pathogenic variants have been described in a number of other genes associated with POI, each with a diagnostic sensitivity of 1-2%. Analysis of the genes BMP15, FSHR as well as INHA, DIAPH2, FOXL2, NOBOX, FIGLA, NR5A1, STAG3, SOHLH1, SOHLH2, GDF9, LHCGR and ESR1 can be requested as part of a gene panel.

 

References
Rossetti et al. 2017, Clin Genet 91: 183 / Ledig et Wieacker 2011, Med Gent 2:237 / Rossetti et al. 2009, Hum Mutat 30:804 / Lussiana et al. 2008, Obstet Gynecol Surv 63:785 / Dixit et al. 2006, Hum Genet 119:408 / Layman 2006, J Clin Endocrinol Metab 91:1673

GENES

FMR1

ASSOCIATED TESTS

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