Genetic modifiers of repeat expansion disorders

Repeat expansion disorders (REDs) are monogenic diseases caused by a sequence of repetitive DNA expanding above a pathogenic threshold. A common feature of the REDs is a strong genotype-phenotype correlation in which a major determinant of age at onset (AAO) and disease progression is the length of the inherited repeat tract. Over a disease gene carrier's life, the length of the repeat can expand in somatic cells, through the process of somatic expansion which is hypothesised to drive disease progression. Despite being monogenic, individual REDs are phenotypically variable, and exploring what genetic modifying factors drive this phenotypic variability has illuminated key pathogenic mechanisms that are common to this group of diseases. Disease phenotypes are affected by the cognate gene in which the expansion is found, the location of the repeat sequence in coding or non-coding regions and by the presence of repeat sequence interruptions. Human genetic data, mouse models and in vitro models have implicated the disease-modifying effect of DNA repair pathways via the mechanisms of somatic mutation of the repeat tract. As such, developing an understanding of these pathways in the context of expanded repeats could lead to future disease-modifying therapies for REDs.

Automated summary

Repeat expansion disorders (REDs) are monogenic diseases caused by repetitive DNA sequences expanding beyond a pathogenic threshold. The length of the repeat sequence is a major determinant of age at onset and disease progression. Phenotypic variability in REDs is influenced by factors such as the gene involved, the location of the repeat sequence, and the presence of interruptions. DNA repair pathways have been identified as potential modifiers of RED phenotypes, offering potential targets for disease-modifying therapies.