The FMR1 gene (Fragile X Mental Retardation type 1; MIM*309550) contains a three nucleotide sequence (CGG) that is repeated between 6 and 44 times. When this number of repeats increases to 55-200 repeats it is called a premutation and becomes unstable when passed on to offspring and can expand to more than 200 repetitions. The result of complete mutation (>200 repeats) is complete silencing of the gene that causes Fragile X syndrome, the most common form of inherited intellectual disability in males. The protein encoded by the FMR1 gene, FMRP, required for cognitive development and also for ovarian development, is predominantly expressed in granulosa cells during normal folliculogenesis and its function appears to depend on an optimal level of transcription.
1 in 150-300 women carry a premutation. Women carrying a premutation may develop early ovarian failure (FXPOI) or decreased ovarian reserve (FXDOR) and are at risk of developing tremor-ataxia syndrome in adulthood. Approximately 20% of women carrying a premutation will develop early ovarian failure. Of women with idiopathic spontaneous premature ovarian failure, 2-6% will have a premutation in FMR1, whereas 14% of women with familial premature ovarian failure will have a premutation in FMR1. Therefore, premutation in the FMR1 gene is the main known heritable cause of both sporadic and familial early ovarian failure.
Approximately 3% of premutation carriers will have irregular menstrual cycles during adolescence and altered hormonal profiles (elevated FSH in the follicular phase and slightly increased AMH levels from the age of 18 compared to non-premutation carriers) supporting that premutation carriers have a diminished ovarian reserve prior to ovarian failure. Despite this decreased ovarian reserve, they do not have an increased risk of miscarriage or chromosomal abnormalities in their offspring, but they do have decreased fertility. Female premutation carriers have a 5-10% risk of having a child with Fragile X syndrome.
Considering its prevalence and serious implications, the ESHRE (European Society of Human Reproduction and Embryology) recommends pre-mutation screening for all women diagnosed with early ovarian failure (elevated FSH in women <40 years) after careful genetic counselling. This pre-test counselling should include education about FMR1-related disorders, discussion of the possibility and implications of detecting a mutation for patients and their families, and review of reproductive options if a premutation is found.
Author: Isabel Ochando