The Relationship Between CAG Repeat Length and Age of Onset Differs for Huntington's Disease Patients with Juvenile Onset or Adult Onset

Abstract

SummaryAge of onset for Huntington's disease (HD) varies inversely with the length of the disease-causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R-squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two-segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log-transformed age of onset against CAG repeat length reveals this segmental relationship. This two-segment exponential regression on age of onset data increases the adjusted R-squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two-segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) = 11.13, P = 2 × 10 − 5 ] and in the HD MAPS cohort [F(2, 688) = 38.27, P = 2 × 10 − 16 ]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult-onset range of CAG repeats than in the juvenile-onset range.

Huntington's Disease: Advocacy Driving Science

“…By using variance-components analysis, we have been able to obtain a more precise estimate of the familiality than previous studies have reported (19,20,23). Surprisingly, even after controlling for the effect of allele length, our results indicate that fully 59% of the variability in residual age of onset is familial and attributable to either genetic or shared environmental factors (15 (15).…”

“…Through studying the Venezuelan kindreds, we showed that the length of the CAG triplet repeat is the most important factor in determining age of onset of HD (13, 17,20,22). We wished to discover if other factors, in addition to the size of the CAG repeat, play a role in determining age of onset.…”

“…Our research goals since initiating the Venezuela Project are multifold: (a) to find the HD gene-which we accomplished (11, 13); (b) to search for genetic and environmental modifiers of HD (15,(17)(18)(19)(20)(21)(22); and (c) to characterize the natural history of HD, providing historical controls for future clinical trials (9,10). We developed a large prospective database containing clinical and genetic information, spanning 23 years, on >2,547 people who have been examined almost every year.…”

A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease

“…Individuals with the juvenile variant of HD typically have an age of onset of under 20 years and can have Ͼ70 CAG repeats (Alonso et al 1997;Sanchez et al 1996;Telenius et al 1993). Whereas a strong relationship is found between age at onset and CAG repeat lengths up to ϳ60, the addition of extra CAG repeats above this seems to have little effect (Andresen et al 2007). Indeed, children with highly expanded CAG repeats show very little variation in age of onset, and those carrying repeats between 100 and Ͼ250 CAG repeats present with symptoms at a similar age (Nahhas et al 2005;Nance et al 1999;Papapetropoulos et al 2005;Seneca et al 2004;Wojaczynska-Stanek et al 2006).…”

Modelling and inference reveal nonlinear length-dependent suppression of somatic instability for small disease associated alleles in myotonic dystrophy type 1 and Huntington disease

“…Levels of somatic mosaicism appear to be relatively lower in small alleles than in long alleles owing to the lengthspecific effect. This gives rise to relatively later ages of onset in small alleles than in long alleles, resulting in the observed nonlinear relationship between age of onset and inherited repeat length [14,45].…”