Interruptions impact clinical features of repeat expansion diseases, but how are they gained and lost?

Trends Genet. 2025 Aug 29:S0168-9525(25)00169-6. doi: 10.1016/j.tig.2025.07.005. Online ahead of print.

ABSTRACT

Interruptions within expanded tandem repeats reduce somatic expansion and alter the severity of the resulting diseases. Consequently, much has been done to identify interruptions in the human population and assess their clinical impact. However, how interruptions are gained and lost is unknown. Here, we propose that synthesis-dependent microhomology-mediated end joining (SD-MMEJ) can account for most, if not all, the dynamic changes in interruptions within expanded repeats. SD-MMEJ explains the locus specificity of interruptions, why they appear near the 5' and 3' ends of expanded tracts, and how complex alleles arise within a single generation. Understanding interruption dynamics is fundamental to repeat expansion disease aetiology and therapeutic development.

PMID:40885674 | DOI:10.1016/j.tig.2025.07.005