Summary

Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associatedwith inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated withdifferent diseases are unrelated and harbor a trinucleotide repeat in different functional regions; therefore, it isstriking that many of these diseases have similar correlations between their genotype, namely the number of inheritedrepeats and age of onset and progression phenotype. These correlations remain unexplained despite more than adecade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of theproposals, being disease-specific, can account for the commonalities among these diseases. Here, we propose auniversal mechanism in which length-dependent somatic repeat expansion occurs during the patient’s lifetime towarda pathological threshold. Our mechanism uniformly explains for the first time to our knowledge the genotype–phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data.In addition, mathematical analysis of the mechanism provides simple explanations to a wide range of phenomena suchas the exponential decrease of the age-of-onset curve, similar onset but faster progression in patients with Huntingtondisease with homozygous versus heterozygous mutation, and correlation of age of onset with length of the short allelebut not with the long allele in Friedreich ataxia. If our proposed universal mechanism proves to be the core componentof the actual mechanisms of specific trinucleotide diseases, it would open the search for a uniform treatment for allthese diseases, possibly by delaying the somatic expansion process.