Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data

Abstract

BackgroundSpinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats (STRs). Recent methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. ObjectivesTo determine the genetic basis of ataxia in a multigenerational Australian pedigree, with autosomal dominant inheritance. Methods and ResultsWGS was performed on three affected relatives. The sequence data was screened for known pathogenic REs using two repeat expansion detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (<five days from receiving the sequencing data) of SCA36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56. Conclusionsthe that diagnosis of rare ataxias caused by REs is highly feasible and cost effective with WGS. We propose that WGS be implemented as the frontline, cost effective methodology for molecular testing of individuals with a clinical diagnosis of ataxia.