One Gene Shuts Down
Fragile X is caused by a mutation in a single gene. In people with Fragile X, a defect (a full mutation) turns the gene off. Like a defective factory, it cannot manufacture the protein that it normally makes.
Fragile X Syndrome is one of the Most Common Rare Diseases
Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and ethnic groups (source CDC). About 1 in 259 women carry fragile X and could pass it to their children. About 1 in 800 men carry Fragile X; their daughters will also be carriers.
Large-scale population studies of Fragile X have not been done, but it clearly it is one of the most common genetic diseases in humans. Fragile X syndrome is the #1 inherited cause of intellectual disabilities and the most common known cause of autism worldwide. Most people with Fragile X are not yet diagnosed.
Simple Cause, Complex Disease
This gene, called FMR1 for Fragile X Mental Retardation–1, was discovered in 1991 by Drs. Ben Oostra, David Nelson, and Stephen Warren. Drs. Oostra, Nelson, and Warren named this mutation FRAXA. It causes almost all cases of Fragile X syndrome.
Fragile X is Inherited
A mother who carries Fragile X has a 50% chance of passing the mutated gene to each of her children. Her children will either be carriers or they will be have Fragile X syndrome.
Carrier men will pass the premutation to all their daughters but none of their sons. These daughters are carriers but they do not have Fragile X syndrome.
The Fragile X premutation can be passed silently down through generations in a family before a child is born with the syndrome.
Carriers, FXTAS, and POI
Carriers have a small mutation in FMR1 (a premutation). Carriers do not show symptoms of fragile X syndrome, but they may be at risk for related disorders such as Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Women who carry Fragile X may be at risk for Primary Ovarian Insufficiency which causes early menopause.
The Centers for Disease Control (CDC) published a study in 2012 which pegs the prevalence of carriers at:
- 1 in 151 females, or about 1 million women in the United States.
- 1 in 468 males, or about 320,000 men in the United States.
The Fragile X Gene
The FMR1 gene is located on the long arm of the X chromosome. At the start of this gene lies a region of DNA which varies in length from one person to another. Ordinarily, this stretch of DNA falls within a range of length that would be considered "normal". In some people, however, this stretch of DNA is somewhat longer; this gene change is a premutation.
Although a person who carries the premutation does not typically have symptoms of Fragile X, the stretch of DNA is prone to further expansion when it is passed from a woman to her children.
When the stretch of DNA expands beyond a certain length, the gene is switched off and does not produce the protein that it is normally makes. This gene change is called a full mutation. A male who inherits a full mutation exhibits Fragile X syndrome because his only X chromosome contains the mutated gene. A female may not be as severely affected because each cell of her body needs to use only one of its two X chromosomes and randomly inactivates the other.