Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications

Short tandem repeats (STRs) are a class of repetitive elements, composed of tandem arrays of 1–6 base pair sequence motifs, that comprise a substantial fraction of the human genome. STR expansions can cause a wide range of neurological and neuromuscular conditions, known as repeat expansion disorders, whose age of onset, severity, penetrance and/or clinical phenotype are influenced by the length of the repeats and their sequence composition. The presence of non-canonical motifs, depending on the type, frequency and position within the repeat tract, can alter clinical outcomes by modifying somatic and intergenerational repeat stability, gene expression and mutant transcript-mediated and/or protein-mediated toxicities. Here, we review the diverse structural conformations of repeat expansions, technological advances for the characterization of changes in sequence composition, their clinical correlations and the impact on disease mechanisms. This Review highlights the diversity in sequence composition of disease-related short tandem repeats. The authors discuss how to detect non-canonical motifs in repeat sequences from sequencing data and review the molecular and clinical consequences of sequence composition changes.