Fragile X syndrome is an inherited condition associated with a range of developmental delays, learning disabilities, thinking (cognitive) impairment and behavioral issues. It is caused by a pathogenic (disease-causing) expansion of repetitive DNA near the FMR1 gene.
Fragile X syndrome is the most common inherited intellectual disability in males, occurring in about 1 in 4,000 males. It also is a significant cause of intellectual disability in females, occurring in approximately 1 in 8,000 females. Up to half of people with fragile X syndrome also have an autism spectrum disorder (ASD). Fragile X syndrome accounts for about 2 to 5 percent of all people with ASD.
Other FMR1-related disorders include:
- Fragile X-associated tremor/ataxia syndrome (FXTAS)
- Fragile X-associated premature ovarian insufficiency (FXPOI)
To learn about fragile X syndrome and related disorders, it is helpful to understand some basics about genetics. Our genetic information is made up of chromosomes that are composed of very long double strands of deoxyribonucleic acid (DNA). Normally, everyone inherits 23 pairs of chromosomes (a total of 46 chromosomes), one set from the mother and the other set from the father. There are twenty-two pairs of chromosomes called autosomes, and two sex chromosomes called X and Y that determine your physical sex at birth. Typically, males have one X and one Y chromosome and females have two X chromosomes.
DNA is made up of specific segments called genes that are composed of multiple chemical "bases" that pair together in a specific pattern. There are four bases: adenine (A), cytosine (C), guanine (G), and thymine (T). Genes serve as templates to make (transcribe) ribonucleic acid (RNA). RNA contains the information for making the proteins that govern how the body works.
The FMR1 gene makes instructions for a protein called FMRP that is necessary for normal brain development. The FMRP protein is involved in developing the specialized connections between nerve cells called synapses. When a change (genetic variant or mutation) near the FMR1 gene disrupts FMRP production, leading to absent or low FMRP levels, it affects the development of the nervous system, resulting in fragile X syndrome.
Very close to the FMR1 gene, there is a section of DNA that has multiple repeats of three DNA bases: cytosine-guanine-guanine (CGG). This is called a CGG triplet repeat.
- Typically, there are between 5 and 44 CGG repeats. This is considered normal. People with this number of repeats are not affected with fragile X syndrome and are not at increased risk of having a child with fragile X syndrome.
- Any variant with more than 44 CGG repeats is called an expansion. Having 45 to 54 CGG repeats is considered an intermediate variant that does not cause fragile X syndrome. A female with a repeat expansion in the intermediate range has a higher chance of passing a larger triplet expansion (a premutation – see below) to her children.
- People with CGG expansions of 55 to 200 repeats are said to have an FMR1 premutation or to be an FMR1 premutation carrier. These individuals may have some signs or symptoms similar to individuals with fragile X syndrome, but these are generally mild and may go unnoticed. The premutation is unstable, which means the number of repeats is likely to increase as it is passed from mother to child. If the number of repeats expands into the full mutation range (200 repeats or greater), it can lead to fragile X syndrome in the child.
- An individual who has more than 200 CGG repeats in this region of DNA is said to have a full mutation. Almost all cases of fragile X syndrome (99%) have an abnormally high number of CGG repeats, usually more than 200. Rarely, fragile X syndrome is caused by a different type of genetic variant, such as an FMR1 gene deletion or a single nucleotide variant. (See the article Genetic Disorders.)
Fragile X syndrome is inherited in an X-linked pattern. The FMR1 gene is located on the X chromosome.
- Mothers pass on only X chromosomes to their children. About 1 in 250 women carry an FMR1 premutation on one of their X chromosomes. With each pregnancy, mothers who are fragile X premutation carriers have a 50 percent chance of passing the X chromosome with the expanded FMR1 gene to their child. When this happens, there is a chance that the number of repeats will grow larger (expand) and surpass 200 when it is passed on, leading to the full mutation variant and fragile X syndrome. The chance that the premutation will expand to the full mutation range when it is passed on depends on its starting size.
- Fathers pass on either an X chromosome or a Y chromosome to their children. Fathers with an FMR1 premutation on their X chromosome will pass it to all their daughters. The premutation is not likely to expand when passed on by fathers and it appears that fathers cannot pass on full mutations to their daughters, but scientists don't understand why. Since Y chromosomes do not have the FMR1 gene, fathers do not pass a premutation or full mutation to their sons.
Since most men have one X chromosome and one Y chromosome, a full mutation or premutation usually affects them more seriously than most women who have two X chromosomes because men do not have a second copy of the gene to make a functioning FMRP protein.