Screening for Fragile X Syndrome (Murray et al.) - NIHR Journals ...

Assessment of screening potentialacceptability of invasive prenatal diagnosis in womenfound to be carriers, and the consequent terminationof pregnancy, would probably be similar tothat found in cascade screening and other studiesof prenatal diagnosis. Hence, about three-quartersof these women would take up prenatal diagnosis(see chapter 9), and nearly all the affected male andhalf the affected female foetuses would be terminated(see Table 10). Thus, if antenatal screening forfragile X syndrome were shown to be acceptable topregnant women, its effectiveness in reducing birthprevalence might be comparable with screening forDown’s syndrome.The feasibility of cascade screening for fragile Xsyndrome rests on the practical experience of thefour studies in which it has been attempted (seepage 33). The most informative study in termsof effectiveness is that from New South Wales.Within the affected families known to the screeningprogramme, there has been a dramatic reductionin affected births both through avoidanceof future pregnancies and through prenataldiagnosis (Robinson et al, 1996). However, thereis no reliable information on the impact of thisscreening on the total population birth prevalenceof fragile X syndrome.Pre-conceptual screeningInsofar as the next step to pre-conceptualscreening is prenatal diagnosis, the same detectionrate, false-positive and predictive values will apply.Some women may avoid further pregnancies as aresult of screening. Strictly, those who would nothave had an affected foetus if they had conceivedconstitute additional false-positives but it wouldbe impractical to take account of this.Effectiveness cannot be estimated at present,although the effect of a positive result on futurereproduction is likely to be similar to that seen withcascade screening. In the absence of pilot studies,it is difficult to judge how feasible and acceptablepre-conceptual screening for fragile X syndromewould be. If the experience with cystic fibrosis(Brock, 1994) is true for all genetic diseases thenantenatal screening is likely to be much moreeffective than pre-conceptual screening.Cascade screeningThe detection rate and negative predictive value ofcascade screening will be similar to pre-conceptualscreening but the other parameters will differbecause the target population are selected becauseof high prior risk. Therefore the positive rate ishigh and, although a large proportion of the PMswill expand, the false-positive rate must be greaterthan in the general population. The positive predictivevalue will be higher too, primarily becauseof the greater prior risk.Paediatric screeningWith paediatric screening, the child is the affectedindividual and a test for the FM will also have anapproximately 100% detection rate and negativepredictive value. The test will only yield a falsepositiveresult if a female has an FM but does nothave fragile X syndrome. Thus, false-positives willbe rare and, assuming that an equal number ofmales and females are tested, the positivepredictive value will be 3 in 4.There is practical experience of paediatric screeningbut its effect on prognosis is unknown. Thereare medical, educational, psychological and socialinterventions which are believed to improve symptoms(see page 6). However, there are no clinicaltrials or other comparable data that can be usedto confirm that early treatment leads to improvedlong-term benefit compared with treatment appliedat the usual time of presentation. Common sensedictates that some benefits will accrue but theyneed to be quantified.Neonatal screeningThe screening performance parameters willbe similar to paediatric screening. There is nopractical experience of this kind of screeningfor fragile X syndrome and, as with paediatricscreening, there is the same problem ofproving effectiveness.44