Screening for Fragile X Syndrome (Murray et al.) - NIHR Journals ...
Screening for Fragile X Syndrome (Murray et al.) - NIHR Journals ... Screening for Fragile X Syndrome (Murray et al.) - NIHR Journals ...
NHS R&D HTA ProgrammeThe overall aim of the NHS R&D Health Technology Assessment (HTA) programmeis to ensure that high-quality research information on the costs, effectiveness andbroader impact of health technologies is produced in the most efficient way for thosewho use, manage and work in the NHS. Research is undertaken in those areas where theevidence will lead to the greatest benefits to patients, either through improved patientoutcomes or the most efficient use of NHS resources.The Standing Group on Health Technology advises on national priorities for healthtechnology assessment. Six advisory panels assist the Standing Group in identifyingand prioritising projects. These priorities are then considered by the HTA CommissioningBoard supported by the National Coordinating Centre for HTA (NCCHTA).This report is one of a series covering acute care, diagnostics and imaging, methodology,pharmaceuticals, population screening, and primary and community care. It was identifiedas a priority by the Population Screening Panel (see inside back cover).The views expressed in this publication are those of the authors and not necessarily thoseof the Standing Group, the Commissioning Board, the Panel members or the Departmentof Health.Series Editors:Assistant Editor:Andrew Stevens, Ruairidh Milne and Ken SteinJane RobertsonThe editors have tried to ensure the accuracy of this report but cannot acceptresponsibility for any errors or omissions. They would like to thank the refereesfor their constructive comments on the draft document.ISSN 1366-5278© Crown copyright 1997Enquiries relating to copyright should be addressed to the NCCHTA (see address given below).Published by Core Research, Alton, on behalf of the NCCHTA.Printed on acid-free paper in the UK by The Basingstoke Press, Basingstoke.Copies of this report can be obtained from:The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 1703 595 639 Email: hta@soton.ac.ukhttp://www.soton.ac.uk/~hta
Health Technology Assessment 1997; Vol. 1: No. 4ContentsList of abbreviations and glossary ..............Executive summary .....................................1 Background ................................................... 1Molecular genetics ......................................... 1Improved diagnosis ........................................ 1Routine screening .......................................... 1Screening policy ............................................. 12 Systematic review ......................................... 33 Natural history ............................................. 5Physical characteristics ................................... 5Cognitive profile ............................................. 5Behavioural features ...................................... 6Treatment ....................................................... 64 Genetics ......................................................... 9Population genetics ........................................ 9Cytogenetics .................................................... 9Molecular genetics ......................................... 10FMR-1 gene ..................................................... 10Normal alleles ................................................ 10Mutated alleles ............................................... 11Grey zone ........................................................ 13Phenotype–genotype relationship ................. 13Cytogenetic–moleculargenetic comparison ....................................... 14Aetiology of the expansion ............................ 145 Definitions ..................................................... 19Affected ........................................................... 19Carrier ............................................................. 19Screening for fragile X syndrome ................. 196 Prevalence .................................................... 21Bias .................................................................. 21Frequency in the mentally handicapped ...... 21General population prevalence ..................... 227 Screening and diagnosis .............................. 25Aims of screening ........................................... 25Screening strategies ....................................... 25Prenatal diagnosis .......................................... 26Pre-implantation diagnosis ............................ 26Case-finding .................................................... 278 Screening and diagnostic tests ................... 29Cytogenetic tests ............................................ 29Southern blotting of genomic DNA ............. 29iiiiDNA amplification by polymerasechain reaction ................................................. 30PCR and selective Southern blotting ............ 30Blotting PCR products ................................... 31PCR-based methylation assay ......................... 31Measurement of FMRP ................................... 31Alternatives to standard PCR ......................... 31Testing protocols ............................................ 319 Practical experience of screeningand diagnosis ................................................. 33Antenatal screening ....................................... 33Pre-conceptual screening .............................. 33Active cascade screening ............................... 33Prenatal diagnosis and terminationof pregnancy ................................................... 34Paediatric screening ....................................... 3510 Modelling allele dynamics ........................... 37A simple model .............................................. 37PM frequency ................................................. 37FM frequency .................................................. 39Risk of expansion from PM to FM in families .. 39Risk of expansion according to PM size ........ 40Risk of expansion in the general population .. 40General population model ............................ 4211 Assessment of screening potential ............ 43Measures of screening performance ............. 43Potential of screening for fragile X syndrome . 43Antenatal screening ....................................... 43Pre-conceptual screening .............................. 44Cascade screening .......................................... 44Paediatric screening ....................................... 44Neonatal screening ........................................ 4412 Human and financial costs of screening ... 45Hazards of prenatal screening ....................... 45Psychological burden ..................................... 45Costs ................................................................ 46Ethics .............................................................. 4713 Recommendations ....................................... 49Acknowledgements ...................................... 51Bibliography ................................................... 53Other references ............................................ 69Health Technology Assessment reportspublished to date ......................................... 71
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He<strong>al</strong>th Technology Assessment 1997; Vol. 1: No. 4ContentsList of abbreviations and glossary ..............Executive summary .....................................1 Background ................................................... 1Molecular gen<strong>et</strong>ics ......................................... 1Improved diagnosis ........................................ 1Routine screening .......................................... 1<strong>Screening</strong> policy ............................................. 12 Systematic review ......................................... 33 Natur<strong>al</strong> history ............................................. 5Physic<strong>al</strong> characteristics ................................... 5Cognitive profile ............................................. 5Behaviour<strong>al</strong> features ...................................... 6Treatment ....................................................... 64 Gen<strong>et</strong>ics ......................................................... 9Population gen<strong>et</strong>ics ........................................ 9Cytogen<strong>et</strong>ics .................................................... 9Molecular gen<strong>et</strong>ics ......................................... 10FMR-1 gene ..................................................... 10Norm<strong>al</strong> <strong>al</strong>leles ................................................ 10Mutated <strong>al</strong>leles ............................................... 11Grey zone ........................................................ 13Phenotype–genotype relationship ................. 13Cytogen<strong>et</strong>ic–moleculargen<strong>et</strong>ic comparison ....................................... 14A<strong>et</strong>iology of the expansion ............................ 145 Definitions ..................................................... 19Affected ........................................................... 19Carrier ............................................................. 19<strong>Screening</strong> <strong>for</strong> fragile X syndrome ................. 196 Prev<strong>al</strong>ence .................................................... 21Bias .................................................................. 21Frequency in the ment<strong>al</strong>ly handicapped ...... 21Gener<strong>al</strong> population prev<strong>al</strong>ence ..................... 227 <strong>Screening</strong> and diagnosis .............................. 25Aims of screening ........................................... 25<strong>Screening</strong> strategies ....................................... 25Prenat<strong>al</strong> diagnosis .......................................... 26Pre-implantation diagnosis ............................ 26Case-finding .................................................... 278 <strong>Screening</strong> and diagnostic tests ................... 29Cytogen<strong>et</strong>ic tests ............................................ 29Southern blotting of genomic DNA ............. 29iiiiDNA amplification by polymerasechain reaction ................................................. 30PCR and selective Southern blotting ............ 30Blotting PCR products ................................... 31PCR-based m<strong>et</strong>hylation assay ......................... 31Measurement of FMRP ................................... 31Alternatives to standard PCR ......................... 31Testing protocols ............................................ 319 Practic<strong>al</strong> experience of screeningand diagnosis ................................................. 33Antenat<strong>al</strong> screening ....................................... 33Pre-conceptu<strong>al</strong> screening .............................. 33Active cascade screening ............................... 33Prenat<strong>al</strong> diagnosis and terminationof pregnancy ................................................... 34Paediatric screening ....................................... 3510 Modelling <strong>al</strong>lele dynamics ........................... 37A simple model .............................................. 37PM frequency ................................................. 37FM frequency .................................................. 39Risk of expansion from PM to FM in families .. 39Risk of expansion according to PM size ........ 40Risk of expansion in the gener<strong>al</strong> population .. 40Gener<strong>al</strong> population model ............................ 4211 Assessment of screening potenti<strong>al</strong> ............ 43Measures of screening per<strong>for</strong>mance ............. 43Potenti<strong>al</strong> of screening <strong>for</strong> fragile X syndrome . 43Antenat<strong>al</strong> screening ....................................... 43Pre-conceptu<strong>al</strong> screening .............................. 44Cascade screening .......................................... 44Paediatric screening ....................................... 44Neonat<strong>al</strong> screening ........................................ 4412 Human and financi<strong>al</strong> costs of screening ... 45Hazards of prenat<strong>al</strong> screening ....................... 45Psychologic<strong>al</strong> burden ..................................... 45Costs ................................................................ 46Ethics .............................................................. 4713 Recommendations ....................................... 49Acknowledgements ...................................... 51Bibliography ................................................... 53Other references ............................................ 69He<strong>al</strong>th Technology Assessment reportspublished to date ......................................... 71
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