A journey through genetic movement disorders caused by non-coding repeat expansions

Abstract

Nucleotide repeat expansions are a key genetic mechanism underlying various neurological disorders, especially in movement disorders. While many expansion-related conditions are caused by variants in coding regions, an increasing number of non-coding repeat expansions have been linked to movement disorders. In this narrative review, we provide an overview of the genotypic and phenotypic features of movement disorders caused by non-coding repeat expansions, highlighting newly identified disorders involving the FGF14, RFC1, GLS, NUTM2B-AS1, NOTCH2NLC, and GIPC1 genes. Accurate diagnosis of these disorders requires repeat-primed PCR, Southern blotting, or long-read sequencing since conventional short-read next-generation sequencing frequently fails to detect pathogenic repeat expansions. Given these challenges, a phenotype-guided targeted genetic testing strategy is proposed to improve diagnostic accuracy in clinical practice. Physicians should be aware of the growing list of movement disorders caused by non-coding repeat expansions, which require a high index of clinical suspicion and specific genetic testing not covered by standard broad genetic panels.