Claudine M Kraan1,2,3, Quang M Bui4, Mike Field5, Alison D Archibald6, Sylvia A Metcalfe7,8, Louise M Christie5, Bruce H Bennetts9, Ralph Oertel10, Melanie J Smith6, Desiree du Sart10, Damien Bruno10, Tiffany L Wotton9,11, David J Amor10,7,12, David Francis10, David E Godler10. 1. Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia. claudine.kraan@mcri.edu.au. 2. Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia. claudine.kraan@mcri.edu.au. 3. School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, Victoria, Australia. claudine.kraan@mcri.edu.au. 4. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia. 5. Genetics of Learning Disability Service (GOLD service), Hunter Genetics, Newcastle, New South Wales, Australia. 6. Reproductive Genetics, Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia. 7. Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia. 8. Genetics Education and Health Research, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia. 9. Sydney Genome Diagnostics-Molecular genetics, Children's Hospital at Westmead, Sydney, New South Wales, Australia. 10. Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia. 11. NSW Newborn Screening Programme, Children's Hospital at Westmead, Sydney, New South Wales, Australia. 12. Developmental Disability and Rehabilitation Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
Abstract
PURPOSE: Developmental delay phenotypes have been associated with FMR1 premutation (PM: 55-200 CGG repeats) and "gray zone" (GZ: 45-54 CGG repeats) alleles. However, these associations have not been confirmed by larger studies to be useful in pediatric diagnostic or screening settings. METHODS: This study determined the prevalence of PM and GZ alleles in two independent cohorts of 19,076 pediatric referrals to developmental delay diagnostic testing through Victorian Clinical Genetics Service (cohort 1: N = 10,235; cohort 2: N = 8841), compared with two independent general population cohorts (newborn screening N = 1997; carrier screening by the Victorian Clinical Genetics Service prepair program N = 14,249). RESULTS: PM and GZ prevalence rates were not significantly increased (p > 0.05) in either developmental delay cohort (male PM: 0.12-0.22%; female PM: 0.26-0.33%; male GZ: 0.68-0.69%; female GZ: 1.59-2.13-%) compared with general population cohorts (male PM: 0.20%; female PM: 0.27-0.82%; male GZ: 0.79%; female GZ: 1.43-2.51%). Furthermore, CGG size distributions were comparable across datasets, with each having a modal value of 29 or 30 and ~1/3 females and ~1/5 males having at least one allele with ≤26 CGG repeats. CONCLUSION: These data do not support the causative link between PM and GZ expansions and developmental-delay phenotypes in pediatric settings.
PURPOSE: Developmental delay phenotypes have been associated with FMR1 premutation (PM: 55-200 CGG repeats) and "gray zone" (GZ: 45-54 CGG repeats) alleles. However, these associations have not been confirmed by larger studies to be useful in pediatric diagnostic or screening settings. METHODS: This study determined the prevalence of PM and GZ alleles in two independent cohorts of 19,076 pediatric referrals to developmental delay diagnostic testing through Victorian Clinical Genetics Service (cohort 1: N = 10,235; cohort 2: N = 8841), compared with two independent general population cohorts (newborn screening N = 1997; carrier screening by the Victorian Clinical Genetics Service prepair program N = 14,249). RESULTS: PM and GZ prevalence rates were not significantly increased (p > 0.05) in either developmental delay cohort (male PM: 0.12-0.22%; female PM: 0.26-0.33%; male GZ: 0.68-0.69%; female GZ: 1.59-2.13-%) compared with general population cohorts (male PM: 0.20%; female PM: 0.27-0.82%; male GZ: 0.79%; female GZ: 1.43-2.51%). Furthermore, CGG size distributions were comparable across datasets, with each having a modal value of 29 or 30 and ~1/3 females and ~1/5 males having at least one allele with ≤26 CGG repeats. CONCLUSION: These data do not support the causative link between PM and GZ expansions and developmental-delay phenotypes in pediatric settings.
Entities:
Keywords:
Developmental delay (DD); fragile X mental retardation 1 gene (FMR1 gene); fragile X syndrome (FXS); premutation; prevalence
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