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

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Screening and diagnostic teststhe number of interrupting AGGs. In case-findingfor cascade screening or in paediatric screening,genomic Southern blotting would be used todetect the FM allele.Prenatal diagnosisThe first prenatal diagnosis of an affected foetuswas made using cytogenetics in amniocytes (Jenkinset al, 1981; Shapiro et al, 1982). Since then, over100 cytogenetic prenatal diagnoses have been madein amniocytes, chorionic villi and foetal blood with,as expected, large numbers of false-negative andfalse-positive results (Jenkins et al, 1995b).There have been no reported diagnostic errorsusing DNA technology in amniocytes (Jenkins etal, 1995b) but care is needed when chorionic villiare analysed. CVS has the advantage over amniocentesisof an earlier and speedier diagnosis butthere are technical problems. Several studieshave reported abnormal methylation patterns inchorionic villi whereby FMs genes are hypomethylatedrelative to foetal tissue (Sutherland et al,1991a; Iida et al, 1994; Castellvi-Bel et al, 1995;Yamauchi et al, 1993; Jenkins et al, 1994b; Sutherlandet al, 1991b). Consequently, lyonisation of theinactive X is not observed and foetal sex determinationrequires additional PCR amplification of X-and Y-specific DNA (Devys et al, 1992). Also, it isdifficult to interpret a band in the PM range whichcould be the result of incomplete methylation ofa FM size mosaic (Strain et al, 1994). In such cases,an amniotic fluid or foetal blood sample would beneeded to determine the full range of the mutationand the methylation status of the foetus. The lattercould only be confirmed by performing a doubledigest using a methylation sensitive restrictionenzyme. Maternal contamination has also beenreported (Maddalena et al, 1994).Pre-implantation diagnosisDreesen and colleagues (1995) suggest thatpre-implantation diagnosis may be performedby genotyping the polymorphic RS46(DXS548)locus, which is closely linked with the FMR-1gene. However, there are two limitations withthis method: a diagnosis cannot be made whenthe paternal and maternal alleles are the sameat this locus or when the female is homozygousat the locus.32

Health Technology Assessment 1997; Vol. 1: No. 4Chapter 9Practical experience of screeningand diagnosisAntenatal screeningThere have not yet been any large-scale,population-based screening programmes inthe general population. However, there issome information from two studies in whichattempts to screen selected populations havebeen made.Fairfax, USAA pilot study was initiated at the end of 1993.All women referred to a genetics institute forprenatal diagnosis were offered screening ona self-pay basis (Howard-Peebles et al, 1995;Spence et al, 1996). The principal reasonfor referral was advanced reproductive age.A total of 3345 pregnant women were offeredthe test, of whom 688 (21%) accepted. A largeproportion (31%) of those accepting the offerhad a family history of mental retardation,learning disability, autism or attention-deficitdisorders, which may have influenced theirdecision. Of the three women who werefound to have a PM, all had an unremarkablefamily history.New York, USAA small antenatal screening programme hasbeen in place since 1992 for women with a familyhistory of learning disability of unknown aetiology(Brown et al, 1996). Some 344 women have beenscreened, but no information is available on thenumber being offered the test. Six women werefound to have FMR-1 mutations – two had an FMand four a PM.Pre-conceptual screeningThere are no reported studies of screening lowrisk populations prior to pregnancy. However,one centre has reported on testing 271 potentialegg donors in an in-vitro fertilisation programme(Spence et al, 1996). One woman was found tohave a PM and another produced a result in thegrey zone, with a repeat size of 52. Both womenwere counselled and offered prenatal diagnosisin a subsequent pregnancy.Active cascade screeningThree fully active screening programmes havebeen reported so far; a fourth did not start bycase-finding among the mentally-handicappedbut used cytogenetic records as its basis, togetherwith an educational campaign among healthcare providers.New South Wales,AustraliaA state-wide screening programme has grown outof the studies aimed at case-finding which werestarted more than 10 years ago in New South Wales,Australia (Turner et al, 1986). Over the years theproject has become a full-scale cascade screeningprogramme, whose stated aim is to informextended families about the reproductive risksbefore childbearing.By 1990, the clinical history of over 14,000intellectually-handicapped individuals, adultsand schoolchildren, had been reviewed and justover half were selected for testing (Turner et al,1992). Permission to test was received from79%, which resulted in 253 putative cases beingidentified, 30% of whom were not already knownto have fragile X syndrome. (Subsequent DNAtesting showed that some of these were falsepositivediagnoses).A case-control study has been carried out toexamine the influence of genetic counsellingon subsequent reproduction among femaleFM and PM carriers identified in the early stagesof the scheme. In 303 case-control pairs, thosegiven counselling had 26% fewer pregnancies(77 versus 104). This reproductive decline wasmost marked in the 85 pairs of women whoalready had an affected child; there were 70%fewer pregnancies (six versus 20). There were77 pregnancies in the women who had beencounselled, and although prenatal diagnosiswas offered, only 61% accepted. Since theintroduction of DNA testing methods, 44 femalecarriers identified by the scheme have subsequentlybecame pregnant (Robinson et al, 1996).All were offered prenatal diagnosis and 34(77%) accepted.33

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