Detection of short tandem repeat expansions on a targeted neurological gene panel using STRipy improves the diagnostic rate for ataxias

Abstract Short tandem repeat expansions are associated with over 50 diseases, many with primary neurological presentations. Despite the prevalence of short tandem repeat expansion disorders, genetically diagnosing these conditions is complicated by a lack of efficient and comprehensive diagnostic screening approaches. We integrated a new short tandem repeat genotyping tool, STRipy, into the analytical workflow for short-read sequencing data generated by the comprehensive neurological disease gene panel used in the Diagnostic Genomics department, PathWest Laboratory Medicine. We tested STRipy on Versions 6 and 7 of the panel. Version 6 already included probes covering five short tandem repeat expansion loci in the following genes: CACNA1A, PPP2R2B, TBP, NOP56 and RFC1. Additional probes targeting 13 neurological disease short tandem repeat expansion loci were designed and included in Version 7. All expansions detected by STRipy were validated and sized using PCR-based diagnostic techniques. Four hundred and eighteen patients with ataxia were tested on Version 6 of the panel, 61 (14.6%) had reportable pathogenic variants, including 11 patients with pathogenic repeat expansions detected by STRipy. Sixty-seven ataxia patients were tested on Version 7 of the panel, 15 (22.4%) had reportable pathogenic variants, including three repeat expansions detected by STRipy. Therefore, STRipy contributed 18.0% and 20.0% of the solved cases from Version 6 and 7 of the ataxia subpanels, respectively. STRipy accurately identified and sized loci with shorter pathogenic repeat thresholds where the expansion was smaller than the read length. In addition to increased diagnostic yield, implementation of STRipy into diagnostic analysis pipelines has streamlined clinical diagnosis of short tandem repeat expansion disorders.