An assessment of screening strategies for fragile X syndrome in the UK

Pembrey M E, Barnicoat A J, Carmichael B, Bobrow M, Turner G
Record ID 32001000057
Authors' objectives:

To assess the feasibility and acceptability of population screening by addressing the following questions in the context of existing services for families with fragile X syndrome.

- Is there a suitable test for all fragile X genotypes? - What are the UK population distribution of FMR1 repeat sizes, and the prevalence of full and premutations in both sexes? - What reliable information, in terms of the chance of an affected child, is available to women with premutations between 55 and 200 repeats? - What is the effect of a premutation on the person who carries it? - What information is available to women with intermediate alleles of 41 to 5460 repeats? - How many affected people are diagnosed? - Given the practice of offering extended family testing (cascade testing), what is the population prevalence of as-yet-undiagnosed female carriers of a full or premutation? What proportion of women at risk can be reached by cascade testing? - What are the costs of fragile X syndrome to an affected person and their family and to the NHS and society? - What is the attitude of families to the benefits and costs of a diagnosis of fragile X syndrome, and to the prospect of population screening? - What data are available from existing population screening programmes? - What alternatives to population screening exist and are these feasible?

Authors' results and conclusions: Unlike cytogenetic approaches, DNA analysis can reliably determine the FMR1 CGG repeat number and detect full mutations; however, a combination of polymerase chain reaction and Southern blotting tests is required, which limits high throughput. There are UK population-based data on FMR1 repeat sizes of up to 60 repeats but insufficient to provide a reliable estimate of the prevalence of premutations (approximately 60-200 repeats). The few data and estimates in the literature of women carriers of the premutation range from 1 in 246 to 1 in 550. Two UK DNA-based estimates of the prevalence of males with the full mutation are 1 in 4090 (Coventry) and 1 in 5530 (Wessex). There are reasonable family-based data for the risk of expansion to a full mutation for the larger premutations but in the 5069 repeat range the estimates are less secure. This is particularly true of the general population, in which limited screening data (approximately 60 transmissions) produced no full mutation. Women with premutations have about a 16% chance of menopause before 40 years of age compared with approximately 1% in the general population. It was suggested by one study that, in boys with special educational needs, those with an intermediate allele (4160 repeats) are over-represented. Probably less than half of those with fragile X syndrome are currently known to UK regional genetics centres. Systematic case-finding, as in New South Wales, Australia, can increase this figure markedly and, coupled with family cascade counselling, can lead to both an increase in reproductive confidence and a 60% reduction in prevalence. Simulations indicate, however, that case-finding and cascade counselling can only reach about half of premutation carriers, although these individuals would include most of those at the highest risk. The costs of fragile X syndrome are as much social as financial and affected families are generally supportive of the idea of screening. Systematic case-finding and cascade testing are a partial alternative to population screening but require more staff, together with laboratory and other consumables, at regional genetics centres to be feasible.
Authors' recommendations: Programmes of systematic case-finding and cascade testing could achieve benefits for those women most at risk. A trial of systematic case-finding and cascade testing to evaluate the benefits and costs of such an approach would be based on reasonably secure risk figures for counselling. The same is not true for a trial of population screening. The uncertainty about the risks for women from the general population with 55-65 repeats can only be resolved with more research. Ongoing research should clarify a possible link between intermediate alleles and learning difficulties.
Authors' methods: Systematic review
Project Status: Completed
URL for project:
Year Published: 2001
English language abstract: An English language summary is available
Publication Type: Not Assigned
Country: England, United Kingdom
MeSH Terms
  • Fragile X Syndrome
  • Mass Screening
Organisation Name: NIHR Health Technology Assessment programme
Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK
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