18 May 2007
Fragile X syndrome is an inherited form of learning disability caused by expansion of a tract of CGG repeats on the X chromosome that leads to methylation and decreased expression of the FMR1 gene. The condition is estimated to affect between 1/4000 and 1/8000 males. Normal individuals have fewer than 45 repeats of the CGG sequence, while affected individuals have more than 200 repeats. Alleles with 55-200 repeats are classed as ‘pre-mutation’ alleles that may expand during female meiosis, so that a woman with a pre-mutation, although herself not usually affected by significant learning disability, is at risk of transmitting a full mutation to her offspring. Males with Fragile X syndrome are generally more severely affected than females. The carrier frequency of Fragile X syndrome in the population is thought to be about 1/100.
Molecular diagnosis of Fragile X carrier status is laborious because techniques based on use of the polymerase chain reaction (PCR) do not work with large tracts of repeated sequence. Researchers at Quest Diagnostics in California have developed a new technique, capillary Southern analysis (CSA), that they claim is rapid, high-throughput, amenable to automation and suitable for use as an initial screening test [Strom CM et al (2007) Genet Med 9, 199-207]. Alleles identified as pre- or full mutations by CSA analysis can be subjected to detailed analysis by Southern blotting to confirm the nature of the mutation and the methylation status of the FMR1 gene. The researchers claim that their protocol detects female carriers with 100% sensitivity and at least 95% specificity, and suggest that the use of CSA as a screening test should enable introduction of a population carrier screening programme for Fragile X syndrome.
Comment: The CSA technique seems likely to be a welcome innovation in the diagnosis of Fragile X carrier status. However, the existence of a rapid screening test is only one of many criteria for a population screening programme, and the issue of antenatal carrier screening for Fragile X is controversial. Although some analyses have found that antenatal carrier screening would be ‘cost-effective’, there are many questions still to be answered. The consequences for a woman of testing positive for a pre-mutation are of particular concern, as the chances of expansion to a full mutation may be as low as 10% in women with no family history of the condition.