Unstable Familial Transmissions of Huntington Disease Alleles With 27-35 CAG Repeats (Intermediate Alleles)

There are inconsistent reports regarding the likelihood of repeat instability for alleles with 27-35 CAG repeats in the Huntington disease (HD) gene. We have examined the intergenerational stability of such intermediate alleles in 51 families from the University of British Columbia's DNA and Tissue Bank for Huntington Disease Research (UBC-HD Databank). A total of 181 transmissions were identified, with 30% (n = 54/181) of the alleles being unstable upon transmission. The unstable transmissions included both expansions (n = 37) and contractions (n = 17) of CAG size. Of the expanded alleles, 68% (n = 25/37) expanded into the HD range (>36 CAG). Therefore, 14% (n = 25/181) of the 27-35 CAG allele transmissions examined expanded into the disease-assodated range resulting in a new mutation for HD. Significantly, of these new mutations, 40% (n = 10/25) originated from an allele with 35 CAG repeats with CAG repeat expansions ranging from +1 CAG to +23 CAG. The proportion of new mutations in the UBC-HD Databank is consistent with the most recent new mutation rate for HD, estimated to be at least 10%. The observed difference in the stability of HD intermediate allele transmissions in this data set and in other studies maybe a reflection of a small sample size. Alternately, these inconsistencies may indicate an underlying difference in genetic factors which influence repeat instability between the different populations examined. Additional studies determining the frequency and magnitude of repeat instability in this CAG repeat range and factors that influence instability are urgently needed. Until we understand the clinical implications of HD alleles with 27-35 CAG repeats and establish reliable risks of instability, we should exercise caution when translating these results to the clinic. (C) 2009 Wiley-Liss, Inc.