Fragile X Syndrome

What is Fragile X syndrome?
What causes Fragile X syndrome?
Who is at risk for Fragile X syndrome?
Why is Fragile X syndrome testing recommended?

What is Fragile X syndrome?
Fragile X syndrome is the most common type of inherited mental retardation.¹ Individuals with fragile X syndrome have mental retardation that ranges from mild to severe. Autistic features with speech and language problems are also common. There is no cure for fragile X syndrome. Approximately 1 in 1500 males and 1 in 2500 females have fragile X syndrome.²

What causes Fragile X syndrome?
Fragile X syndrome is caused by a genetic problem on the X chromosome. Chromosomes are the units of heredity. People get half of their chromosomes from their mothers and half of their chromosomes from their fathers. Women have two X chromosomes, and men have an X chromosome and a Y chromosome.

The X chromosome carries the gene for fragile X syndrome. Genes are the instructions that tell our bodies how to function. They are made from DNA. The fragile X syndrome gene has a "fragile" site.² A fragile site on the chromosome can only be seen in the laboratory after special chemical treatment. This was how the syndrome got its name. The length or amount of DNA at the fragile site can vary.¹ The length of this site is measured by special laboratory DNA testing techniques² and is reported as "repeats."¹

The number of repeats varies (Table 1). Individuals with fewer than 44 repeats are considered "normal."³ When 45 to 54 repeats are found, the individual is considered borderline normal. It is highly unlikely that individuals with 45 to 54 repeats will have a child with fragile X syndrome, but it is a possibility that the fragile X gene in their family is not stable, and future generations could be at risk for fragile X syndrome. Family studies are necessary to determine the stability of the gene.³ People with 55 to 200³ repeats are considered carriers and generally do not have any symptoms of fragile X syndrome. Cases of more than 200 repeats are considered full mutations. A full mutation may result in fragile X syndrome.²

Table 1—DNA Repeats as Indicators of Fragile X Disease Severity*

*From Maddalena A, Richards CS, McGinnis MJ, et al. Technical standards and guidelines for fragile X: The first of a series of disease-specific supplements to the standards and guidelines for clinical genetics laboratories of the American College of Medical Genetics. Genet Med. 2001; 3(3):200-205.

Who is at risk for Fragile X syndrome?
The inheritance of fragile X syndrome is complex. Expansion of the fragile X premutation into a full mutation has only been reported when the premutation is passed on by the mother.^2,3 Therefore, a woman that is a carrier of fragile X syndrome has a 50% chance with each pregnancy to pass on the unstable fragile X gene.³ The chance that the unstable gene will expand into a full mutation varies with the repeat size.¹

Males can also be carriers of fragile X syndrome, but in general the fragile X gene is not expected to expand into the affected range when passed on through the male.³ Men who are carriers of fragile X syndrome are called "transmitting males."¹ Men pass the Y chromosome to their sons; therefore, no son will inherit the fragile X gene from his father. Men pass the X chromosome to their daughters. Consequently, under normal circumstances, all of the daughters of a male carrier of fragile X syndrome will also be carriers.³ These daughters will be at increased risk to have affected children.

Table 2—DNA Repeats Related to Disease Risk in Offspring**

**From Fu Y-H, Kuhl DPA, Pizzuti A, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell. 1991; 87:1047-1058.

Why is Fragile X syndrome testing recommended?
DNA testing is available to determine if a person is affected with fragile X syndrome or is a carrier.² The American College of Medical Genetics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG) have recommended^2,4 that testing for fragile X syndrome be offered to any child who has developmental delay or mental retardation (of no obvious reason), autistic-like features, or other physical findings and behavior consistent with fragile X syndrome. Any person who is considering a pregnancy or is pregnant should be offered carrier screening for fragile X syndrome if there is a family history of fragile X syndrome or a family history of male or female relatives with undiagnosed mental retardation.² Prenatal diagnosis is available for fragile X syndrome.³ Several options for testing are available. The most common tests are amniocentesis and chorionic villus sampling (CVS). These tests have different risks, benefits, and limitations that should be discussed with the appropriate health care provider.

Summary
Fragile X syndrome is the most common inherited form of mental retardation. Individuals with fragile X syndrome may have a range of symptoms that can include developmental delay, mental retardation, and autistic features. Fragile X syndrome is inherited in an X-linked manner. It is caused by a mutation on the X chromosome. Nearly all affected people and most carriers inherited the fragile X gene from their mothers. Men who are carriers will not likely have affected children, but all of their daughters will be carriers. Testing is recommended for individuals who appear to have symptoms consistent with fragile X syndrome. Testing for carrier status should be offered to all persons who have a family history of fragile X syndrome or have male or female relatives with undiagnosed mental retardation. Prenatal diagnosis is available.

References

1. Fu Y-H, Kuhl DPA, Pizzuti A, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell. 1991; 87:1047-1058.
2. American College of Obstetricians and Gynecologists. Fragile X syndrome (1995) ACOG Committee Opinion; Number 161, October, 1995.
3. Maddalena A, Richards CS, McGinnis MJ, et al. Technical standards and guidelines for fragile X: The first of a series of disease-specific supplements to the standards and guidelines for clinical genetics laboratories of the American College of Medical Genetics. Genet Med. 2001; 3(3):200-205.
4. ACMG Policy Statement: Fragile X syndrome diagnostic and carrier testing. Am J Med Gen. 1994; 53:380-381.