Unstable familial transmissions of Huntington disease alleles with 27–35 CAG repeats (intermediate alleles)

Abstract

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-associated 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 may be 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.

REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review

“…The authors suggest that 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 (Semaka et al, 2010).…”

“…Studies that had examined the degree of instability of IA familial transmission have curious findings (Brocklebank et al, 2009;Semaka et al, 2010). In a Venezuelan family, no de novo mutation was documented within 69 transmissions of IAs (Brocklebank et al, 2009).…”

“…In a Venezuelan family, no de novo mutation was documented within 69 transmissions of IAs (Brocklebank et al, 2009). On the other hand, 14% of the same kind of transmissions led to expansions, in future generations, in 51 families from Northern Europe (Semaka et al, 2010).…”

CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease

“…Clinical risk assessment for repeat expansion should also account for sex of the transmitting parent and CAG size. Unfortunately, risk estimates for repeat instability during maternal transmission remain limited to previously published familial transmission studies and additional studies aimed at establishing empirical female-specific risk estimates are needed 12. Men found to have an IA predictive test result may be provided CAG size-specific risk estimates based on the data presented here and the magnitude of expansion could also be discussed.…”

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

“…29 The new mutation rate has been estimated at approximately 10%. 30,31 Factors influencing the expansion of the CAG tract are therefore of crucial importance for determining HD prevalence rates. The size of the CAG repeat and the sex of the transmitting parent are known to have a significant role in CAG-tract instability.…”