Fragile X syndrome

A test to confirm the diagnosis of Fragile X syndrome or determine whether a person is a premutation carrier to diagnose FXPOI (Fragile X-associated primary ovarian insufficiency) and FXTAS (Fragile X-associated tremor/ataxia syndrome).

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What is fragile X syndrome?

Fragile X syndrome (FXS, also known as Martin—Bell syndrome) is a hereditary disease that causes a number of cognitive, behavioral and intellectual impairments. FXS is caused by the mutations in FMR1 gene through the expansion of CGG repeats, deletions or point mutations. The majority of detected aberrations (99%) are the expansion of CGG repeats, which increases the risk of gene silencing.

FXS has an X-linked dominant inheritance. As males have only one X chromosome, syndrome symptoms are more severe and more frequent (1 in 3,600 males). Meanwhile females, who carry two X chromosomes, typically have a milder phenotype or have no symptoms at all (1 in 6,000 females).

X-linked dominant inheritance

Number of CGG repeats vary and can change as the gene is passed from one generation to another. A fragile X carrier is an individual that carries an altered FMR1 gene, but does not show any symptoms. Women who are fragile X carriers have up to 50% risk of having a son with fragile X syndrome, and up to 50% risk to have a daughter with carrier status. Men carriers on the other hand, will pass the altered gene to all of their daughters but none of their sons.

X-linked inheritance in fragile X syndrome

Approximately 1 in 250 women and 1 in 800 men in general population are Fragile X premutation carriers, which can lead to the following CGG repeat expansion in the next generation. Fragile X carrier can be anyone and is found among all ethnic backgrounds and racial groups.

1 in 250 women/1 in 800 menare Fragile X premutation carriers

Symptoms

There is a range of symptoms caused by Fragile X syndrome. Abilities range from mild learning disabilities to severe mental retardation. Behavioral characteristics include autism, hyperactivity, short attention span and poor eye contact. Physical features, such as large ears, long face, flat feet and enlarged testes are more noticeable in young adults than children.

Some carriers are at risk of developing disorders which are associated with the Fragile X premutation. Elderly men may develop tremor/ataxia syndrome (FXTAS) — tremors, wobbly gait, and speech may suffer. Women may experience primary ovarian insufficiency (FXPOI) — diminished ovarian reserve and early menopause, or neuropsychiatric disorders (FXAND) — include anxiety, depression, thyroid problems, auto-immune issues, fibromyalgia, migraines and sleep disturbance. It is important to note that an experiences of each individual can be different.

Fragile X Associated Primary Ovarian Insufficiency (FXPOI)

Fragile X associated primary ovarian insufficiency is a condition that affects women and is caused by a premutation in their FMR1 gene. The ovaries of individuals with FXPOI prematurely slow down in overall function, including their ability to maintain and release eggs, resulting in reduced fertility. Common symptoms of FXPOI include irregular or absent menstrual cycles, early menopause (before the age of 40), infertility and elevated levels of a follicle stimulating hormone (FSH).

Some studies have shown that about 20-25% of women who are fragile X premutation carriers develop FXPOI. The risk of POI is dependend on the number of CGG repeats, with peak risk at 80-100 repeats. It has been shown that approximately 5% of primary ovarian insufficiency cases are associated with the expansion in FMR1 gene.

20-25% of female carriers develop primary ovarian insufficiency, which can be cause of infertility

It is essential to identify women who carry a premutation and are at risk for developing diminished ovarian function. While there is not cure for FXPOI, early diagnosis allows them to make an timely decision regarding their reproductive and family planning.

Currently, FMR1 premutation carriers who wish to conceive and avoid the risk of having an affected child have three options:

To conceive with the help of IVF and preimplantation genetic testing for monogenic gene diseases (PGT-M).
Spontaneous conception and prenatal testing through amniocentesis or chorionic villus sampling (CVS) to evaluate the genetic status of pregnancy.
Using a donor oocyte.

Indications for the study

This test may be recommended for individuals with specific symptoms to confirm the diagnosis or for those who want to know the potential genetic risks when planning a child.

You are at greater risk to be a fragile X carrier if you have:

A family history of fragile X syndrome
A family history of mental retardation, developmental delay or autism of unknown cause
Infertility problems associated with elevated follicle stimulating hormone (FSH) levels or premature ovarian failure
A family history of adult onset ataxia and/or tremors

It is important to emphasize that females who are premutation carriers are at great risk of having a child with disorder, especially in the case of sons. Expansion to the full mutation typically only occurs through female transmission. Males with the premutation are not shown to be at risk of having affected children, but their daughters are. Diagnostic genetic screening for FMR1 gene can be used to detect premutation in women before conception, which allows the parents to know their risk of having a child with Fragile X syndrome.

Method (Carrier testing for FXS)

Number of CGG repeats in the FMR1 gene is one of the key targets for carrier screening. Fragile X carrier test provides information whether or not individuals are fragile X carriers, and about their risks of having a child with fragile X syndrome. Results provided by the testing are proven to be accurate 99 percent of the time.

99% test accuracy

Testing is performed using dual PCR system combining full length and triplet primed PCR amplification (TP-PCR), followed by fragment analysis to measure repeat sections of DNA associated with diseases, including Fragile X syndrome. Test allows to accurately and consistently detect and classify alleles as Normal, Intermediate, Premutation and Full Mutation.