Detection and discovery of repeat expansions in ataxia enabled by next-generation sequencing: present and future.

Abstract

Hereditary cerebellar ataxias are a heterogenous group of progressive neurological disorders that are disproportionately caused by repeat expansions (REs) of short tandem repeats (STRs). Genetic diagnosis for RE disorders such as ataxias are difficult as the current gold standard for diagnosis is repeat-primed PCR assays or Southern blots, neither of which are scalable nor readily available for all STR loci. In the last five years, significant advances have been made in our ability to detect STRs and REs in short-read sequencing data, especially whole-genome sequencing. Given the increasing reliance of genomics in diagnosis of rare diseases, the use of established RE detection pipelines for RE disorders is now a highly feasible and practical first-step alternative to molecular testing methods. In addition, many new pathogenic REs have been discovered in recent years by utilising WGS data. Collectively, genomes are an important resource/platform for further advancements in both the discovery and diagnosis of REs that cause ataxia and will lead to much needed improvement in diagnostic rates for patients with hereditary ataxia.