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Reduced penetrance alleles for Huntington’s disease: a multi-centre direct observational study
  1. Oliver W J Quarrell1,
  2. Alan S Rigby2,
  3. L Barron3,
  4. Y Crow4,
  5. A Dalton5,
  6. N Dennis6,
  7. A E Fryer7,
  8. F Heydon8,
  9. E Kinning9,
  10. A Lashwood10,
  11. M Losekoot11,
  12. L Margerison12,
  13. S McDonnell13,
  14. P J Morrison14,
  15. A Norman15,
  16. M Peterson16,
  17. F L Raymond17,
  18. S Simpson18,
  19. E Thompson19,
  20. J Warner3
  1. 1Department of Clinical Genetics, Sheffield Children’s (NHS) Trust, Sheffield, UK
  2. 2Academic Department of Cardiology, University of Hull, Kingston-upon-Hull, UK
  3. 3Human Genetics Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK
  4. 4Molecular Medicine Unit, St James Hospital, Leeds, UK
  5. 5Department of Molecular Genetics, Sheffield Children’s (NHS) Trust, Sheffield, UK
  6. 6Department of Clinical Genetics, Princess Anne Hospital, Southampton, UK
  7. 7Department of Clinical Genetics, Royal Liverpool Children’s Hospital (Alder Hey), Liverpool, UK
  8. 8Department of Clinical Genetics, The Churchill Hospital, Oxford, UK
  9. 9Leicestershire Genetics Centre, Leicester Royal Infirmary, Leicester, UK
  10. 10Department of Genetics, Princess Anne Hospital, Southampton, UK
  11. 11Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  12. 12Department of Genetics, Kennedy Galton Centre, Northwick Park and St Marks Hospitals, Harrow, UK
  13. 13Institute of Human Genetics, Newcastle upon Tyne, UK
  14. 14Department of Clinical Genetics, Belfast City Hospital Trust, Belfast and Division of Biomedical Sciences, University of Ulster, Coleraine, UK
  15. 15Clinical Genetics, Birmingham Women’s Hospital, Edgbaston, Birmingham, UK
  16. 16South West Thames Regional Genetics Service, Medical Genetics Unit, St George’s Hospital, University of London, London, UK
  17. 17Department of Medical Genetics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
  18. 18Department of Medical Genetics, Medical School, Forresterhill, Aberdeen, UK
  19. 19SA Clinical Genetics Service, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia
  1. Correspondence to:
 Oliver Quarrell
 Department of Clinical Genetics, Sheffield Children’s Hospital, Western Bank, Sheffield, S10 2TH, UK; oliver.quarrell{at}sch.nhs.uk

Abstract

Objective: To obtain penetrance data for Huntington’s disease when DNA results are in the range of 36–39 CAG repeats and assess the consistency of reporting the upper allele from two reference centres.

Method: Data were collected anonymously on age of onset or age last known to be unaffected from a cohort of individuals with results in this range. DNA samples were re-analysed in two reference centres. Kaplan-Meier analysis was used to construct an age of onset curve and penetrance figures.

Results: Clinical data and concordant DNA results from both reference centres were available for 176 samples; penetrance figures (and 95% confidence intervals) for this cohort, at age 65 and 75 years, were 63.9% (55.5% to 73.2%) and 74.2% (64.2% to 84.2%), respectively. Inclusion of 28 additional subjects for whom repeat DNA results were unavailable, obtained from only one reference centre, or discrepant by one repeat within this range, gave penetrance data (including 95% confidence intervals) at ages 65 and 75 years of 62.4% (54.4% to 70.4%) and 72.7.% (63.3% to 82.1%), respectively. 238 duplicate results were available from the reference centres; 10 (4.2%) differed by one CAG repeat in the reporting of the upper allele and in two (0.84%) of these cases the discrepancy was between 39 and 40 repeats.

Conclusion: When DNA results are in this range, a conservative approach is to say that there is at least a 40% chance the person will be asymptomatic at age 65 years and at least a 30% chance the person will be asymptomatic at age 75 years.

  • Huntington’s disease
  • penetrance
  • 36–39 repeats

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Footnotes

  • This work was funded from a grant by Action Medical Research.

  • Competing interests: None declared.

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