Fragile X Syndrome
The fragile X Syndrome is the most frequent cause of inherited mental retardation, affecting approximately 1 in 1,250 males and 1 in 2,000 females. In affected individuals, the mutation causes difficulties ranging from mild learning disabilities to severe mental retardation and autism. The variable clinical expression makes the inheritance pattern unusual and complex. All mothers of affected males must be assumed to be carrier and about one third of the carrier females are retarded, although more mildly than affected males. Only 30%-50% of carrier females show fragile sites. The diagnosis of fragile X Syndrome has important prognostic implications for the individual and reproductive implications for the family. The molecular diagnostic techniques allow identification of both affected individuals and carriers. The test is also available for prenatal diagnosis.
Molecular basis
Fragile X is an X-linked disorder (Xq27.3) with an unusual inheritance pattern in which both males and females can be either affected or normal carriers. The gene underlying the fragile X syndrome (FMR-1 gene) was identified in 1991. The disorder is caused by an expansion of a DNA triplet repeat in the upstream region of the FMR-1 gene, represented as (CGG)n with n=6 to 52 on normal chromosomes. Fragile X premutation carriers have between 52 and 200 copies of repeats. Affected individuals have greater than 200 copies (full mutation) of repeat. The gene frequency of the fragile x premutation is estimated to be about 1 in 500. Premutations do not produce any phenotypic effect in carrier. The number of amplified repeats has a high probability of increasing in the next generations. The larger size of the premutation repeat has a higher risk to become a full mutation in the next generation. The nature of the mutation, and the possibility that the repeat expands in successive generations explains why normal males can transmit this X-linked trait (“normal transmitting males”).
It has been shown that the CGG repeat sequence is usually interrupted by two interspersed AGGs, whereas 70% of premutation alleles contain a single AGG interruption and loss of AGG triplets, leading to long uninterrupted tracts of CGG triplets, is characteristic of a premutation alleles.
Mosaicism can occur both in males and females. The clinical features may vary in such patients. Although the exact function of the FMR-1 gene product is not known, it is likely that the increased length of the mutation and an accompanying methylation of this region causes the gene to become inactive.
Mutations other than the CGG expansion are known but are considered very rare.
Indications for testing
- For a diagnosis of fragile X in males with mild to severe mental retardation or learning disabilities, with or without the (physical) characteristics associated with fragile X : Macrocephaly or normocephaly, long face, large ears, prominent jaw, hyperactivity, short attention span, tactile defensiveness, hand biting, poor eye contact, preservative speech, large testicles. The mental and behavioural disabilities are often more consistent in prepubertal males than are the physical features.
- To determine a diagnosis of fragile X in families with two or more individuals with mental retardation.
- To detect the presence of the fragile X mutation in at-risk females within a fragile X family. Female carriers have a 50 % risk of passing the abnormal gene to their offspring. The severity of the syndrome in the affected child is a function of the length of the expansion of the triplet repeat.
- To identify normal transmitting males : These males will pass the premutation to all their daughters. While these carrier females are normal, they are at risk for producing affected children due to the expansion of the repeat through female meiosis.
Sample Requirements
DNA
Whole blood:
- to be collected in lavender-top (EDTA) tubes
Prenatal Specimens:
- 20 ml of unspin amniotic fluid;
10 mg of clean wet weight chorionic villi.
Contact us: Tel:(+98 21)88003811-12