Contents
Introduction
So called as there is a ‘fragile site’ on the X chromosome. This is a non-staining, weakened section of the chromosome which is susceptible to breaking.
It is an example of a trinucleotide expansion mutation, but is usually inherited in an X-linked recessive pattern.
Fragile X syndrome is the second most common cause of genetic learning difficulty after Down’s Syndrome.
Epidemiology
- Affects 1 in 5000 males
- The most common INHERITED cause of learning difficulty
- Accounts for 4-8% of all male learning difficulty
- Female carriers may show a mild form of the disease (in around 50% of cases)
Clinical features
Prominent Facial Features
- High forehead
- Large ears – often the most obvious sign
- Long face
- Prominent jaw
After Puberty
- Large testes
Connective tissue signs
- Hyperextensible joints
- Stretch marks (striae)
- Mitral valve prolapsed
Learning difficulties
- Usually moderate to severe – often show autistic tendencies
- IQ may be 20-80, mean of 50
- May shoe hyperactive behaviour
In female cariers
- Mild facial features may be present
- May have reduced intellectual capacity
Cytogenetics
- An example of a trinucleotide repeat expansion mutation
- These mutation typically become more severe in successive generations
- It is passed on in an X-linked recessive pattern
- The fragile part of the chromosome is sometimes known as the FRAXA mutation. At this point there is a large CGG repeat sequence. In normal people, this sequence is 10 to 50 repeats long. In some individuals it is 50 to 200 repeats long. This makes this section unstable.
- This type of instability as a result of repetition is known as premutation. The individuals are not affected, but have a high risk of having affected children.
- In fragile X syndrome, the repeat is >200 repeats long.
- The condition usually develops in the following manner:
- A male with the premutation passes this on to all his daughters. Usually none of these patients will have clinical effects.
- The female carriers are phenotypically unaffected now have a high risk of having a son with fragile X syndrome, as the repeat section is likely to be lengthened during meiosis. Any sequence of >100 repeats carries a high risk of having an affected child.
- This is sometimes called expansion of the triplet sequence.
- FRAXA is responsible for about 75% of cases of fragile X syndrome
- FRAXE is another similar repeat sequence which is responsible for about 25% of cases of the syndrome. The repeat sequence is the same (CGG) but is in a different location on the chromosome.
- FRAXE patients tend to have less severe learning difficulties
- FRAXF is another similar site, however defects here do not appear to cause an clinical abnormality.
- Symptoms are seen in:
- Women with the full mutation – usually mild – about 50% of cases
- All men with the full mutation
- Never seen as a de novo mutation – and thus all mothers of affected children are carriers
- As it is x-linked recessive:
- All daughters of an affected male will be carriers
- All sons of an affected male will be normal – fathers pass on the Y chromosome to their sons.
Genetic counseling for fragile X syndrome
- The inheritance pattern is atypical x- linked.
- As the condition is a major cause of learning difficulties, genetic counselling of affected individuals and carriers of the premutation is appropriate.
- Women who carry the fully affected gene (>200 repeats)
- 50% risk if her child is male
- Women who carry the fully affected gene
- 25% risk of having a daughter with learning difficulties
- Chorionic villus sampling is able to tell if the defect is present
- However, if the child is female, then the phenotype cannot be determined by this method