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Fragile XE syndrome
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Reviewed January 2014
What is fragile XE syndrome?
Fragile XE syndrome is a genetic disorder that impairs thinking ability and cognitive functioning. Most affected individuals have mild intellectual disability. In some people with this condition, cognitive function is described as borderline, which means that it is below average but not low enough to be classified as an intellectual disability. Females are rarely diagnosed with fragile XE syndrome, likely because the signs and symptoms are so mild that the individuals function normally.
Learning disabilities are the most common sign of impaired cognitive function in people with fragile XE syndrome. The learning disabilities are likely a result of communication and behavioral problems, including delayed speech, poor writing skills, hyperactivity, and a short attention span. Some affected individuals display autistic behaviors, such as hand flapping, repetitive behaviors, and intense interest in a particular subject. Unlike some other forms of intellectual disability, cognitive functioning remains steady and does not decline with age in fragile XE syndrome.
How common is fragile XE syndrome?
Fragile XE syndrome is estimated to affect 1 in 25,000 to 100,000 newborn males. Only a small number of affected females have been described in the medical literature. Because mildly affected individuals may never be diagnosed, it is thought that the condition may be more common than reported.
What genes are related to fragile XE syndrome?
Fragile XE syndrome is caused by mutations in the AFF2 gene. This gene provides instructions for making a protein whose function is not well understood. Some studies show that the AFF2 protein can attach (bind) to DNA and help control the activity of other genes. Other studies suggest that the AFF2 protein is involved in the process by which the blueprint for making proteins is cut and rearranged to produce different versions of the protein (alternative splicing). Researchers are working to determine which genes and proteins are affected by AFF2.
Nearly all cases of fragile XE syndrome occur when a region of the AFF2 gene, known as the CCG trinucleotide repeat, is abnormally expanded. Normally, this segment of three DNA building blocks (nucleotides) is repeated approximately 4 to 40 times. However, in people with fragile XE syndrome, the CCG segment is repeated more than 200 times, which makes this region of the gene unstable. (When expanded, this region is known as the FRAXE fragile site.) As a result, the AFF2 gene is turned off (silenced), and no AFF2 protein is produced. It is unclear how a shortage of this protein leads to intellectual disability in people with fragile XE syndrome.
People with 50 to 200 CCG repeats are said to have an AFF2 gene premutation. Current research suggests that people with a premutation do not have associated cognitive problems.
Read more about the AFF2 gene.
How do people inherit fragile XE syndrome?
Fragile XE syndrome is inherited in an X-linked dominant pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females.
In parents with the AFF2 gene premutation, the number of CCG repeats can expand to more than 200 in cells that develop into eggs or sperm. This means that parents with the premutation have an increased risk of having a child with fragile XE syndrome. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons; sons receive a Y chromosome from their father, which does not include the AFF2 gene.
Where can I find information about diagnosis or management of fragile XE syndrome?
These resources address the diagnosis or management of fragile XE syndrome and may include treatment providers.
General information about the diagnosis and management of genetic conditions is available in the Handbook. Read more about genetic testing, particularly the difference between clinical tests and research tests.
To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.
Where can I find additional information about fragile XE syndrome?
You may find the following resources about fragile XE syndrome helpful. These materials are written for the general public.
You may also be interested in these resources, which are designed for healthcare professionals and researchers.
What other names do people use for fragile XE syndrome?
What if I still have specific questions about fragile XE syndrome?
Where can I find general information about genetic conditions?
The Handbook provides basic information about genetics in clear language.
These links provide additional genetics resources that may be useful.
What glossary definitions help with understanding fragile XE syndrome?
alternative splicing ; cell ; chromosome ; disabilities ; disability ; DNA ; gene ; hyperactivity ; inheritance ; inherited ; mental retardation ; mutation ; premutation ; protein ; sex chromosomes ; sign ; sperm ; splicing ; syndrome ; trinucleotide repeat ; X-linked dominant
You may find definitions for these and many other terms in the Genetics Home Reference Glossary.
See also Understanding Medical Terminology.
References (4 links)
The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.