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Genewatch: Screening for Fragile-X Syndrome

Health Technology Assessment is an important part of the NHS R&D programme. It aims to ensure that high quality information on the costs, effectiveness and broad impact of health technologies is collected and disseminated to those who work in, and manage the NHS. Research is targeted to those areas where new evidence should lead to the greatest benefits to patients and the most efficient use of NHS resources.

HTA report

A recently published report commissioned by the HTA programme sets out the current state of knowledge about screening for the fragile-X syndrome. The work reported involved a comprehensive systematic review of over 500 papers on the subject. Its stated purpose was to provide the information needed to decide whether to use DNA testing to screen for the disorder. In this it is, not surprisingly, only partly successful. Most of its recommendations are for further studies because current information isn't adequate to allow rational decisions to be made about future screening strategies.


Fragile-X syndrome is the second most common cause of severe mental retardation after Down's syndrome. The latest population prevalence figures are about 1 in 4,000 for males and 1 in 8,000 for females. About 6% of institutionalised individuals with learning difficulties have the syndrome. It was first described in 1969 and the responsible gene, FMR-1, was identified in 1991. In addition to varying degrees of mental retardation the clinical phenotype often includes macro-orchidism in males, abnormal facies with prominent forehead, large jaw and large ears, joint laxity and behavioural problems. The syndrome gets its name from the fact that chromosomal analysis usually reveals a narrowing near the end of the long arm of the X chromosome (Xq27).

Fragile-X is one of a small group of genetic disorders where the abnormality is an unstable non-Mendelian mutation with an increased number of copies of a specific repeated trinucleotide sequence. It displays unusual inheritance patterns for an X-linked disease in that males can be phenotypically normal carriers of the pre-mutation (as shown in the Table below, with a comparison with Huntingdon's disease and myotonic dystrophy), and their children are not at an increased risk of the disorder. In contrast the children of female carriers are at an increased risk, since the pre-mutation is less stable and more likely to increase in repeat size in females. Females may be affected, but are usually less severely mentally retarded than affected males.

Characteristics of commonest Trinucleotide Repeat Syndromes
Fragile-X syndrome Huntington's disease Myotonic dystrophy
approximate prevalence 1 in 4,000 1 in 20,000 1 in 25,000
age of onset congenital 30 to 55 congenital or mid-life
nucleotide sequence CCG CAG CTG
no. copies 'normal' 6 to 50 9 to 34 5 to 30
no. copies 'pre-mutation' /carrier 50 to 200 50 to 80
no. copies full mutation /cases 200 - 000's 37 to 80 up to 2000
gene name FMR -1 HD MD
chromosome site Xq27.3 4p16.3 19q13.2
OMIM gene number 309550 143100 160900
The recommendations made in the report are:-
  1. Cascade screening (ie in affected families) should be regarded as of proven benefit, but national audit of current practice is needed
  2. Paediatric screening - studies are needed to assess current practice
  3. Antenatal screening - the practicality, acceptability and cost of routine antenatal screening should be assessed
  4. The psychosocial consequences of being identified as a 'carrier' should be studied
  5. A central register for all diagnoses should be established.


These recommendations reflect the dilemmas faced by almost all new genetic screening programmes. While we now have the technology to undertake sophisticated DNA screening and we know that the incidence of new cases can be reduced, we have little sound information on the human costs of population screening programmes or the real cost/benefits to the NHS. It is critically important that these questions are addressed.

The costs to prevent one affected birth through pre-natal diagnosis in two cascade screening programmes have been reported as $14,200 (Australia, 1986 prices) and $12,740 (US, 1992 prices). It has also been estimated that the lifetime costs of care for an affected individual are in the region of $1-2 million.


  1. Murray J, Cuckle H, Taylor G, Hewison J. Screening for Fragile X syndrome. Health Technology Assessment 1997; 1(4).

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