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Men with FMR1 premutation alleles of less than 71 CGG repeats have low risk of being affected with fragile X-associated tremor/ataxia syndrome (FXTAS)
  1. Ellenore M Martin1,
  2. Ying Zhu1,2,
  3. Claudine M Kraan3,4,
  4. Kishore R Kumar5,6,
  5. David E Godler3,4,
  6. Michael Field1
  1. 1Genetics of Learning Disability (GOLD) Service, Hunter Genetics, Newcastle, New South Wales, Australia
  2. 2Randwick Genomics Laboratory, NSW Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia
  3. 3Diagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia
  4. 4Department of Paediatrics, The University of Melbourne Faculty of Medicine Dentistry and Health Sciences, Parkville, Victoria, Australia
  5. 5Molecular Medicine Laboratory and Neurology Department, Concord Repatriation General Hospital, Concord Clinical School, The University of Sydney, Sydney, New South Wales, Australia
  6. 6Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
  1. Correspondence to Ms Ellenore M Martin, Genetics of Learning Disability (GOLD) Service, Hunter Genetics, Newcastle, New South Wales, Australia; ellenore.martin{at}health.nsw.gov.au

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset condition characterised by cerebellar ataxia and intention tremor, usually found in individuals with FMR1 premutation alleles (PM—CGG expansion of 55–199 repeats). Population studies estimate that between 1 in 250 and 1 in 1600 men have a PM, with up to 45% of these men suggested to develop FXTAS by age 80. We used a Bayesian approach to compare the probability of finding a specific PM genotype in an ataxia population to a population control group and found an estimated penetrance of <1% (0.031%; CI 0.007% to 0.141%) for men with ≤70 CGGs. These findings suggest that men with a PM of ≤70 CGGs, who comprise the vast majority of those with a PM, have a much lower risk of being affected with FXTAS than previously suggested. This is an issue of growing importance for accurate genetic counselling, as those with a PM of ≤70 CGGs are increasingly detected through community carrier screening or neurodevelopmental assessment programmes.

  • DNA repeat expansion
  • human genetics
  • neurodegenerative diseases
  • genetic counseling

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Footnotes

  • Correction notice This article has been corrected since it was published Online First. A typographical error in the "Correspondence to" section has been corrected.

  • Contributors EM and MF formulated the presented idea. EM performed the literature review and collation of data. ZY performed data analysis and computation. EM wrote the inital manuscript with support from MF. CK, DG and KK reviewed the initial manuscript critically and provided important intellectual content. All authors discussed the results and contributed to the final manuscript.

  • Funding KRK receives funding from the Paul Ainsworth Family Foundation, the Michael J. Fox Foundation, Aligning Science Across Parkinson’s (ASAP) initiative and honorarium from Seqirus Australia. CMK is funded by a National Health and Medical Research Council Early Career fellowship (1120561). DEG is funded by the Medical Research Future Fund (MRF1141334).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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