GC-rich repeat expansions: associated disorders and mechanisms

Abstract

Abstract Noncoding repeat expansions are a well-known cause of genetic disorders mainly affecting the central nervous system. Missed by most standard technologies used in routine diagnosis, pathogenic noncoding repeat expansions have to be searched for using specific techniques such as repeat-primed PCR or specific bioinformatics tools applied to genome data, such as ExpansionHunter. In this review, we focus on GC-rich repeat expansions, which represent at least one third of all noncoding repeat expansions described so far. GC-rich expansions are mainly located in regulatory regions (promoter, 5′ untranslated region, first intron) of genes and can lead to either a toxic gain-of-function mediated by RNA toxicity and/or repeat-associated non-AUG (RAN) translation, or a loss-of-function of the associated gene, depending on their size and their methylation status. We herein review the clinical and molecular characteristics of disorders associated with these difficult-to-detect expansions.