Myotonic dystrophy type 1 (DM1) is the most frequent cause of adult muscular dystrophy. It is a progressive multisystem disorder with an incidence of 1 in 8000 newborns. Its molecular basis is an expansion of a CTG repeat in the 3′ untranslated region (UTR) of the DMPK gene on chromosome 19.¹ Fragile X syndrome is the most common inherited cause of mental retardation. It is caused by an expansion of a CGG repeat in the 5′ UTR of the FMR1 gene.^2,3 The full mutation appears in approximately 1 in 4000 males and 1 in 9000 females. The number of trinucleotide repeats (TNRs) in most unaffected individuals is in the range of 5–35 repeats in DM1 and around 14–35 repeats in fragile X syndrome. However, pathogenic loci bear expanded alleles of up to several hundred or even thousand repeats in severe cases.^1,2,4,5

As with many other tandemly repeated microsatellite sequences, pathogenic TNRs are highly unstable in both the somatic and germ cell lineage, leading to expansions and contractions in the length of the repeats in successive cell or individual generations.^6–8 Expansions in the number of TNRs are known to be a molecular basis of genetic anticipation,⁹ the progressively earlier age of onset of a disease with increasing severity in successive generations. An important consequence of genetic anticipation is that the genetic transmission is interrupted and, therefore, new pathogenic alleles have to be generated from unexpanded alleles. Little is known, however, about the mechanism(s) that cause a stable, non-expanded allele to become unstable and pathogenic, probably because normal length alleles are thought to be stable compared with expanded pathogenic alleles. In addition, much of the evidence for the mechanisms that are thought to produce repeat expansion in pathological TNRs are dismissed as …