Inherited CAG.CTG allele length is a major modifier of somatic mutation length variability in Huntington disease.

Huntington disease (HD) is associated with an unstable trinucleotide CAG.CTG repeat expansion. Although the repeat length is inversely correlated with the age-at-onset of symptoms, variability between patients who have inherited the same HD repeat length clearly suggests that other factors influence this aspect of the disease. As repeat length profiles in somatic tissues suggest that repeat length gains may contribute to both the tissue-specificity and progressive nature of HD pathogenesis, genetic modifiers of mutation length variability may therefore influence the age-at-onset of the disease. Using a sensitive single molecule-PCR assay we show that HD mutation length profiles in buccal cell DNA vary from individual to individual. The resulting data provide the first quantitative evidence that inherited CAG.CTG repeat length has a major influence on somatic CAG.CTG repeat length variation. In addition, we confirm that further environmental and/or genetic modifiers of repeat length variation exist and discuss the implications that our results may have on understanding the factors that influence severity and age-at-onset of Huntington disease symptoms.