High frequency of intermediate alleles on huntington disease-associated haplotypes in British Columbia's general population
Article first published online: 30 AUG 2013
© 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 162, Issue 8, pages 864–871, December 2013
How to Cite
2013. High Frequency of Intermediate Alleles on Huntington Disease-Associated Haplotypes in British Columbia's General Population. Am J Med Genet Part B 9999:864–871., , , , , .
- Issue published online: 4 NOV 2013
- Article first published online: 30 AUG 2013
- Manuscript Accepted: 11 JUL 2013
- Manuscript Received: 16 OCT 2012
- Canadian Institutes of Health Research
- Michael Smith Foundation for Health Research
- Huntington disease;
- intermediate alleles;
- new mutations;
- CAG repeat instability;
- genetic counseling
Intermediate alleles (27–35 CAG, IAs) for Huntington disease (HD) usually do not confer the disease phenotype but are prone to CAG repeat instability. Consequently, offspring are at-risk of inheriting an expanded allele in the HD range (≥36 CAG). IAs that expand into a new mutation have been hypothesized to be more susceptible to instability compared to IAs identified on the non-HD side of a family from the general population. Frequency estimates for IAs are limited and have largely been determined using clinical samples of HD or related disorders, which may result in an ascertainment bias. This study aimed to establish the frequency of IAs in a sample of a British Columbia's (B.C.) general population with no known association to HD and examine the haplotype of new mutation and general population IAs. CAG sizing was performed on 1,600 DNA samples from B.C.'s general population. Haplotypes were determined using 22 tagging SNPs across the HTT gene. 5.8% of individuals were found to have an IA, of which 60% were on HD-associated haplotypes. There was no difference in the haplotype distribution of new mutation and general population IAs. These findings suggest that IAs are relatively frequent in the general population and are often found on haplotypes associated with expanded CAG lengths. There is likely no difference in the propensity of new mutation and general population IAs to expand into the disease range given that they are both found on disease-associated haplotypes. These findings have important implications for clinical practice. © 2013 Wiley Periodicals, Inc.