title: CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine & Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Alicia
authors.initials: A
authors.lastname: Semaka
authors.forename: Chris
authors.initials: C
authors.lastname: Kay
authors.forename: Crystal
authors.initials: C
authors.lastname: Doty
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Collins
authors.forename: Emilia K
authors.initials: EK
authors.lastname: Bijlsma
authors.forename: Fiona
authors.initials: F
authors.lastname: Richards
authors.forename: Y Paul
authors.initials: YP
authors.lastname: Goldberg
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000483:Alleles; D005787:Gene Frequency; D042822:Genomic Instability; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D013094:Spermatozoa / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
keywords: CAG repeat instability; Genetic counselling; Huntington disease; Intermediate alleles; New mutations