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CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease
  1. Alicia Semaka1,
  2. Chris Kay1,
  3. Crystal Doty1,
  4. Jennifer A Collins1,
  5. Emilia K Bijlsma2,
  6. Fiona Richards3,
  7. Y Paul Goldberg1,4,
  8. Michael R Hayden1
  1. 1Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
  2. 2Department of Clinical Genetics, Centre for Human and Clinical Genetics, Leiden University Medical Centre (LUMC), Leiden, South Holland, The Netherlands
  3. 3Department of Clinical Genetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
  4. 4Xenon Pharmaceuticals Inc., Burnaby, British Columbia, Canada
  1. Correspondence to Dr Michael R Hayden, Centre for Molecular Medicine & Therapeutics, Child & Family Research Institute, Department of Medical Genetics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4; mrh{at}cmmt.ubc.ca

Abstract

Introduction New mutations for Huntington disease (HD) occur due to CAG repeat instability of intermediate alleles (IA). IAs have between 27 and 35 CAG repeats, a range just below the disease threshold of 36 repeats. While they usually do not confer the HD phenotype, IAs are prone to paternal germline CAG repeat instability. Consequently, they may expand into the HD range upon transmission to the next generation, producing a new mutation. Quantified risk estimates for IA repeat instability are extremely limited but needed to inform clinical practice.

Methods Using small-pool PCR of sperm DNA from Caucasian men, we examined the frequency and magnitude of CAG repeat instability across the entire range of intermediate CAG sizes. The CAG size-specific risk estimates generated are based on the largest sample size ever examined, including 30 IAs and 18 198 sperm.

Results Our findings demonstrate a significant risk of new mutations. While all intermediate CAG sizes demonstrated repeat expansion into the HD range, alleles with 34 and 35 CAG repeats were associated with the highest risk of a new mutation (2.4% and 21.0%, respectively). IAs with ≥33 CAG repeats showed a dramatic increase in the frequency of instability and a switch towards a preponderance of repeat expansions over contractions.

Conclusions These data provide novel insights into the origins of new mutations for HD. The CAG size-specific risk estimates inform clinical practice and provide accurate risk information for persons who receive an IA predictive test result.

  • Huntington disease
  • Intermediate alleles
  • CAG repeat instability
  • New mutations
  • Genetic counselling

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