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

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Practical experience of screening and diagnosisNew York State, USAIn 1987, a programme of cascade screeningwas started in seven regions of New York State(Nolin et al, 1991; 1992). Mentally-impaired,post-pubertal males from institutions andcommunity residences were considered fordiagnostic testing. Physical examinations werecarried out to select those who might havefragile X syndrome and, as a result, 42% weretested. By 1991, 43 cases had been identifiedin 38 families. Of the 33 families followed-upso far, in order to offer genetic counselling,appropriate relatives could not be found fornine and, of the remainder, 12 (50%) tookup the offer.Murcia, SpainIn 1986, a programme of cascade screening wasbegun in the southern Spanish region of Murcia.Index cases were found in special schools andsheltered workshops. The medical records wereexamined in an attempt to preselect those fordiagnostic testing. In the event, the records werenot good enough to enable such a selection tobe made, so most males were selected. A total of22 cases were found, out of 223 males tested, andthe cascade screening used these together witha further 31 males referred directly to the geneticservices. Overall figures on the uptake rate ofgenetic counselling are not available but, inthe 18 families identified from cases in specialschools, 11 (61%) accepted referral; those thatdid not had no appropriate relatives or hadbeen sterilised.Kuopio, FinlandAn attempt has been made to systematically testthe families of index cases diagnosed since 1991in Kuopio, Finland (Ryyänen et al, 1995). Fromcytogenetic records, 28 probands were identifiedand, following a campaign to raise awarenessamong relevant health care providers, a further31 were found. In each family a contact wasapproached, usually a parent or guardian, andasked to make arrangements for other familymembers to be contacted. On the basis of thepedigree, a total of 1017 relatives were identifiedwho had at least a one in eight chance of havingfragile X syndrome. Of the 48% who agreed tobe tested, 72 (14%) were found to have an FMand 163 (32%) a PM. Of the unaffected femaleswith an FM or PM who were identified as a result,21 subsequently became pregnant. All acceptedprenatal diagnosis and the nine foetuses with anFM were terminated. Twelve of these women hadno previous knowledge that they were at highrisk of having an affected pregnancy.Prenatal diagnosis andtermination of pregnancyIt is to be expected that most of those undergoinginvasive prenatal diagnosis for fragile X syndromeTABLE 10 Prenatal diagnosis † of a female foetus with an FM – outcome of pregnancy. Results from seven studiesStudy Number Outcomeof pregnanciesBirth Termination UnknownFrance 3 1 1 1Devys et al, 1992USA, NY I 4 1 3 0Brown et al, 1993Finland 2 2 0 0von Koskull et al, 1994USA, Fairfax 6 2 0 4Maddalena et al, 1994Finland, Kuopio 6 0 6 0Ryynänen et al, 1995USA, NY II 20 7 13 0Brown et al, 1996, plus personal communicationItaly 6 2 4 0Grasso et al, 1996Total 47 15 (32%) 27 (57%) 5 (11%)34† Using DNA technology.
Health Technology Assessment 1997; Vol. 1: No. 4will opt to terminate the pregnancy if the foetushas an FM and is male. The reverse might beexpected in female foetuses with an FM, butthis is not born out by the published studies. InTable 10, the combined results from seven studiesfor the outcome of pregnancy are shown for atotal of 47 such foetuses. Over half are known tohave opted for termination and, excluding thoseof unknown outcome, the proportion increasesto 64%.Paediatric screeningReferralA working group from the American College ofMedical Genetics (1994) has published guidelinesto aid clinicians in making referrals for fragile Xtesting. The group recommends that individualsof either sex with mental retardation, developmentaldelay, or autism be referred, especiallyif features of the disorder are present or thereis a family history of fragile X syndrome or anyother mental abnormality. Thus, in New Mexico(Kaplan et al, 1994), of 271 individuals tested atone laboratory, 61% were referred because ofmental retardation, 27% for developmental delayand 4% for attention-deficit disorders. Only 5%had a family history of fragile X syndrome. AnFM was found in 11 individuals, of whom sevenwere from the 11 referrals with a family historyof fragile X syndrome.In the UK, children with learning difficulties ordevelopmental delay who are referred to geneticscentres usually have tests to exclude fragile Xsyndrome. Since DNA testing became possible,samples are generally being sent to regional DNAlaboratories for testing. There are no publisheddata on the numbers of samples tested for thecountry as a whole but some regional figures areavailable. In Leeds, we have tested samples fromabout 1500 boys, five of whom were found to havean FM. Of 153 girls referred for testing, none hadan FM. Similar results were obtained in Edinburghwhere, over a 5-year period, about 1000 boys havebeen referred and 18 FMs detected (ProfessorDJH Brock, personal communication). Moredetails of referral patterns have come from theSouth East Thames Regional Cytogenetics Laboratory(Barnicoat et al, 1993). Of 680 referrals, halfwere for developmental delay, 79% were male, 17%were related and 3% had pedigrees already knownto be affected. As a result, 17 individuals, all male,were diagnosed as having fragile X syndrome.It is not known to what extent this diagnostictesting leads to cascade screening, active orotherwise. In Strasbourg, France, Mandel andcolleagues (1994) have used DNA methods since1991 to test individuals referred because ofmental retardation. Over the first 2 years, about5% of those tested had an FM. Consequently,38 female carriers were identified in 28 familiesof the probands. It is unclear why there is a higherrate of FM in this study compared with the UKstudies. However, the referring doctors includedclinical geneticists, and there was a requirementto complete a clinical evaluation form for eachreferral, which may have resulted in a degreeof pre-selection.ActiveHagerman and colleagues (1994b) carried out apilot project to determine the feasibility of usingspecial education personnel to select and screenschoolchildren at high risk of fragile X syndrome.The project was carried out in five Colorado, USA,school districts. The first stage was to train teachers,and other professionals who have contact withpupils needing special education, to use a physicaland behavioural checklist. Those determined to beat high risk were, with parental consent, screenedusing a mouthwash sample. Of the 439 pupilstested so far, one-third of whom are girls, 51% hada learning disability and 35% had an attentiondeficitdisorder. Only four of those tested hadan FM, a mosaic male and three females, and allexcept one of the females were already knownto local paediatric services.35
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