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

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Screening and diagnosis26extended to include those with a family history ofmental retardation in general, possibly includingnon-specific or mild disability.Pre-conceptual testingLow risk females of reproductive age would beencouraged to undertake testing for a PM or FM.In a properly constituted screening programme ofthis kind, a target population would be identifiedand systematically offered the test. Possible targetpopulations would include school leavers, womenof reproductive age on general practitioners’lists, and women attending family planningclinics. Experience of pre-conceptual screeningfor another genetic disorder, cystic fibrosis, isthat the uptake rate for testing is lower than forantenatal screening, even though it offers morereproductive choice (Brock, 1994).Cascade screeningFollowing the clinical diagnosis of an affectedindividual, the genetic services normally offercounselling and DNA testing to family members.Close relatives are tested first and, depending onthe results, more distant relatives might be contacted.This is a well-established approach in clinicalgenetics and some would not regard it as screeningper se. With cystic fibrosis screening, a distinctionhas been made between this practice and a moreactive type of cascade testing whereby a systematicapproach is made to identify all affected families.Active cascade screening in its most complete formbegins with a concerted attempt at case-finding.This may involve systematic testing at institutionsand special schools in the area (see page 27).Paediatric testingIt is established practice for paediatricians torequest cytogenetic tests on children referredto them because of developmental delay. Bloodsamples from children with this indication areusually tested for Down’s syndrome and fragileX syndrome. Since the new molecular genetictechnology has become available, fragile Xsyndrome testing is starting to be performedin DNA rather than cytogenetic laboratories.Many diagnoses are made in this manner butthey tend to be the more severe cases.In the UK, a system exists in schools whereby aformal statement is made by the local educationauthority when a child is considered to have aspecial educational need. Paediatricians maycontribute to the assessment on which the statementis based but this is not routine practice. The1981 Education Act requires that needs identifiedin such a statement are met. It is not known whatproportion of children with fragile X syndrome willhave such a statement made. Also, there is often aconsiderable delay before the formal statement ismade. In order to produce a substantial increasein the number of early diagnoses, a more systematicand active approach is needed. One possibilitywould be to alert teachers to specific cognitiveand behavioural traits that indicate a high riskof the disorder.Neonatal testingIn the UK, all newborn infants are subjectto routine testing for phenylketonuria andhypothyroidism using a heal prick blood sampleabsorbed on to a Guthrie card. Increasingly, somecentres are using spare blood spots on the card totest for cystic fibrosis and it would be technicallyfeasible to further extend such testing to includefragile X syndrome.Prenatal diagnosisFemales discovered to have a PM or FM throughantenatal screening or as a result of any of theother screening strategies described above willhave the option of prenatal diagnosis. Foetal DNAcan be obtained from any one of three differentinvasive procedures, namely amniocentesis,chorionic villus sampling (CVS) and peripheralumbilical cord blood sampling (PUBS). Eachprocedure has its own technical limitations andhazards, and these are discussed later.The DNA test on the foetal material obtained atprenatal diagnosis also has its limitations. The testcan only determine whether or not the foetus hasan FM. If it is a male foetus this is equivalent todiagnosing fragile X syndrome. However, only halfthe female foetuses with an FM will have the disorder.Those accepting an offer of prenatal testing,need to give considerable thought to how they willproceed if a female FM carrier is detected. In additionto the options to terminate or continue withthe pregnancy, which also apply to male foetuses,there is a third possibility. They could agree inadvance only to be informed that there is an abnormalityif the foetus is male. In view of this problemand other considerations (discussed in chapter 12),genetic counselling prior to prenatal diagnosis inwomen with a PM or FM is particularly difficult.Pre-implantation diagnosisThe detection of inherited diseases in very earlyembryos allows the selection and transfer of only one
Health Technology Assessment 1997; Vol. 1: No. 4healthy zygote to the uterus. After pre-implantationdiagnosis, couples with a high prior risk can embarkon the pregnancy with the certainty that it is freefrom the specific condition in the family.This service is currently available for cystic fibrosisand X-linked diseases. For fragile X syndrome suchtesting has been done in research laboratories andis likely to become more generally available in thefuture. If the mother has an FM, any zygotes whichalso have an FM need not be transferred. If she hasa PM there are two possibilities; either to avoid usingany mutated zygotes or to reject only those with anFM. If there are not enough good quality zygotes,the latter option might have to be adopted. However,expansion may not have taken place in the blastomere(see page 14) and, if there is a later expansionto FM, the foetus may have fragile X syndrome.improved by carrying out a prior screening of thetarget population to identify those at increasedrisk of fragile X syndrome and to focus testingon this subgroup. Medical records and directexamination of the individuals can be used.Several physical and behavioural checklists havebeen developed for this purpose (Laing et al,1991; Hagerman et al, 1991; Butler et al, 1991b;Nolin et al, 1991; Gabarron et al, 1992). Discriminantanalysis on the items listed shows that mostaffected males can be identified by using relativelyfew of them. For example, Butler and colleagues(1991b) found that five physical criteria, togetherwith a family history of learning disabilities, wouldcorrectly classify over 90% of affected males. Theseinclude the presence of plantar crease, simiancrease, macro-orchidism (mainly post-pubertal),large or prominent ears and hyper-extensibility.Case-findingActive cascade screening is dependent on findingindex cases. The efficiency of this step can be27
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