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

Health Technology Assessment 1997; Vol. 1: No. 4Executive summaryBackground and aim of reviewIn 1991, the gene responsible for fragile Xsyndrome, a common cause of learning disability,was discovered. As a result, diagnosis of the disorderhas improved and its molecular geneticsare now understood. This report aims to providethe information needed to decide whether to useDNA testing to screen for the disorder.How the research was conductedA literature search of electronic reference databasesof published and ‘grey’ literature was undertakentogether with hand searching of the mostrecent publications.Research findingsNatural historyPhysical characteristics of fragile X syndromeinclude facial atypia, joint laxity and, in boys,macro-orchidism. Most affected males havemoderate-to-severe learning disabilities withIQs under 50 whereas most females have borderlineIQs of 70–85. Behavioural problems aresimilar to those seen with autism and attentiondeficitdisorders.Although fragile X syndrome is not curable thereare a number of medical, educational, psychologicaland social interventions that can improvethe symptoms.About 6% of those with learning disabilities testedin institutions have fragile X syndrome. Populationprevalence figures are 1 in 4000 in males and 1 in8000 in females.GeneticsThe disorder is caused by a mutation in a gene onthe X chromosome which includes a trinucleotiderepeat sequence. The mutation is characterised byhyper-expansion of the repeat sequence leading todown-regulation of the gene. In males an allele withrepeat size in excess of 200, termed a full mutation(FM), is always associated with the affected phenotype,whereas in females only half are affected.Individuals with alleles having repeat size in therange 55–199 are unaffected but in females thesequence is heritably unstable so that it is at highrisk of expansion to an FM in her offspring. Thisallele is known as a pre-mutation (PM) to contrast itwith the FM found in the affected individual. Nospontaneous expansions directly from a normalallele to an FM have been observed.Screening strategiesThe principal aim of screening for fragile Xsyndrome is to reduce the birth prevalence ofthe disorder, by prenatal diagnosis and selectivetermination of pregnancy, or by reducing thenumber of pregnancies in women who have theFM or PM alleles.Possible screening strategies are: routine antenataltesting of apparently low risk pregnancies, preconceptualtesting of young women, and systematictesting in affected families (‘cascade’ screening).A secondary aim is to bring forward the diagnosisof affected individuals so that they might benefitfrom early treatment. Active paediatric screeningand neonatal screening could achieve this butthere is no direct evidence of any great benefitfrom early diagnosis.Screening testsCytogenetic methods are unsuitable for screeningpurposes. Southern blotting of genomic DNAcan be used but is inaccurate in measuring thesize of small PMs, there is a long laboratory turnroundtime, and it is relatively expensive. The bestprotocol is to amplify the DNA using polymerasechain reaction on all samples and, when thereis a possible failure to amplify, a Southern blot.Practical experienceThere is little published information on thepractical consequences of offering antenatalor pre-conceptual screening.In one study, antenatal tests were offered to womenabout to have prenatal diagnosis for other conditions.They had to pay for themselves to be testedand uptake was only 21%. In another study, testingwas offered to those with a family history of mentalretardation but the uptake rate was not reported.Pre-conceptual screening has only beenreported among potential egg donors forin vitro fertilisation.iii