In the early 1990s, it was discovered that apparently normal trinucleotide repeats commonly dispersed throughout the genome may expand into impressive lengths, leading to disease.1 This discovery revealed a new mechanism for the genetic origin of several disorders that had remained unexplained by conventional mutational mechanisms. Strikingly, these pathological repeat expansions not only occur in the coding regions, where most disease-causing mutations are found, but also happen in introns and untranslated regions of the gene. Generally, the noncoding CGG/CCG repeats are associated with fragile chromosome syndromes (X, 11B, 16A, etc), whereas the coding CAG/CTG repeats lead to neurodegenerative disorders.2 The expansion of CAG trinucleotide repeat motifs, which encode tracts of the amino acid glutamine, is associated with polyglutamine diseases.3 Clearly, if there is a pathogenic range of expansion, there is also a “normal” range. Generational transmission of repeats that are within these normal ranges tends to be very stable. However, when the repeat number exceeds a certain threshold, depending on the disease, genomic instability and conformational protein changes arise.4 A phenotypic consequence of this is genetic anticipation, where there is an observed increase in severity and decrease in the age of disease onset in successive generations.5 Unusual patterns of inheritance, where the progeny presents de novo expansion mutations, are recognized.6
Hammer MB, Singleton AB. Common Premutations in the General Population. JAMA Neurol. Published online April 01, 201976(6):639–640. doi:10.1001/jamaneurol.2019.0216
Customize your JAMA Network experience by selecting one or more topics from the list below.
Create a personal account or sign in to: