Background
Fragile X syndrome (FXS) is an inherited disorder that causes
learning difficulty. The disorder affects an estimated one in 4000 males and
one in 8000 females. Affected males are generally unable to live independently,
while affected females have learning difficulty but may live independently.
There is no cure for FXS. Management of affected individuals is through specific
educational and psychosocial interventions and treatment of any clinical symptoms.
There are about 10,000 FXS patients in England and Wales.
Since the annual cost to the NHS for managing a moderately affected adult
was approximately £20,000 (1995 data), the total annual cost of managing FXS
patients can be estimated to be £200 million in England and Wales.
FXS is caused by a mutation of the FMR1 gene, which
is located in the Xq27.3 region of the long arm of the X chromosome. It contains
a variable trinucleotide repeat [cytosine–guanine–guanine (CGG)] which can
become unstable over successive generations. The number of CGG repeats within
a gene will determine whether the individual has a normal allele (<55 repeats),
premutation (55–200 repeats) or a full mutation (>200 repeats). All males
with full mutation (FM) and about half of females with FM are affected with
learning difficulty. People with premutation (PM) are not affected in general.
The PM can become unstable on maternal transmission and mothers with PM may
have affected children. The risk of expansion from PM to FM depends on the
number of CGG repeats in the maternal allele and other factors. The expansion
risk from PM to FM is much greater in affected families than in the general
population.
Options for population and targeted screening for FXS and
carriers have been the focus of two previously published HTA reviews. However,
the two previous HTA reports reached contrasting conclusions and recommendations
for further research. The different approaches recommended by the two HTA
reviews were prenatal screening of all apparently low-risk women, and cascade
testing of high-risk women following systematic case finding. This review
aims to bring together the findings of the two previous HTA reports.
Methods
We first conducted an assessment of published literature,
to bring together and update the findings of two previous HTA reviews. Then
efforts were focused on the development of a model (the FXS Model) that could
be used to compare the cost-effectiveness of active cascade screening of affected
families and population based prenatal screening for FXS. The assumptions
about input parameters to the FXS Model were based on a comprehensive literature
review and the model’s test running.
Major findings
Prevalence
The overall prevalence of FXS was on average 2.3%, ranging
from 0.3% to 16% in males with learning difficulty. Preselection according
to family history and clinical features can increase the proportion of detected
FXS cases among people with learning difficulty who were DNA tested. Using
the indirect method and data from eight studies, the prevalence of FXS in
the general population was estimated to be 2.3/10,000 (or 1 in 4425).
Pooling data from identified studies (16 for males and 14
for females), the prevalence of PM was 0.16% (1 in 643) among the general
male population and 0.67% (1 in 149) among the general female population.
These may have overestimated the prevalence of PM in the general population
because of the possible founder effect and biased selection in screening programmes.
The estimated prevalence of PM was sensitive to the cut-off value of CGG repeat
size used to define the PM. The PM repeat sizes in the general population
were generally much smaller than those in the affected families.
Risk of expansion from PM to FM
The risk of expansion from PM to FM in maternal transmission
is related to the size of CGG repeats and the risk of expansion from PM to
FM in the general population is significantly lower than that in FXS families.
Based on data of 1111 maternal PM transmissions, the pooled rate of expansion
from PM to FM was 63.4% [95% confidence interval (CI): 60.5 to 66.2%] in PM
carriers from FXS families. According to data of 183 maternal PM transmissions,
the pooled rate of expansion from PM to FM was 9.8% (95% CI: 5.5 to 14.2%)
in PM carriers identified from the general population.
Feasibility and acceptability
The empirical evidence suggested that preconceptual or prenatal
screening, case finding and cascade screening are feasible and acceptable
by affected families and by the general population. The identified screening
programmes were effective in detecting carriers, but a comparison of different
strategies was not possible.
Findings of the FXS Model
Simulation results by the FXS Model showed that, over the
first 10 years, 4% of PM females and 70% of FM females could be detected by
active cascade screening; it is 10% and 58%, respectively, by prenatal screening.
The maximal detection rate for FM carriers by active cascade screening is
slightly higher than that by prenatal screening (91% versus 71%). However,
the maximal rate of detection of female PM carriers by active cascade screening
(6%) is much lower than that by prenatal screening (60%). During the first
10 years of simulation, the additional number of births of FXS children that
can be avoided each year is estimated to be about 15 (range: 4–31) by active
cascade screening, and about 39 (range: 9–76) by prenatal screening.
Due to the fact that the screening candidates need to be
tested only once, the total number of women with unknown carrier status will
be reduced by the screening programmes. During the first 10 years, the estimated
direct cost per year to the NHS in England and Wales is £0.7–0.2 million by
active cascade screening and £14.5–9.1 million by a programme of prenatal
screening. The incremental cost per extra carrier detected (using current
practice as the reference standard) is on average only £165 (range: £129–182)
by active cascade screening and £7543 (range: £5316–14,636) by prenatal screening.
The incremental cost per FXS birth avoided is on average £8494 (range: £1367–27,314)
by active cascade screening and £284,779 (range: £135,510–950,572) by prenatal
screening.
Considering that the lifetime care of each FXS patient will
cost the NHS about £380,000, the most expensive strategy (population prenatal
screening) is still cost-saving in the long term. The estimated net savings
per year in England and Wales are about £10 million by active cascade screening
and about £8 million by prenatal screening.
Conclusions
The empirical evidence suggested that both prenatal screening
and cascade screening are feasible and acceptable. Both prenatal screening
and active cascade screening can reduce the number of births of FXS children
and are cost-saving in the long term. Population-based prenatal screening
is more efficacious and has a greater impact on the population, but it will
also cost more than active cascade screening. The active cascade screening
of affected families is more efficient, cheaper, but less effective than a
population-based prenatal screening.
Since both prenatal screening and active cascade screening
have advantages and disadvantages, we believe that both strategies should
be evaluated in large-scale trials. It may also be important to explore and
evaluate whether and how the different strategies could be simultaneously
or sequentially combined.
Publication
Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.
Screening for fragile X syndrome: a literature review and modelling study.
Health Technol Assess 2003;7(16).
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