In the cases where we made an eventual diagnosis, the delay was 3–35 years (mean 18.1 years). The delays were primarily related to lack of easily available clinical testing, but other factors included the presence of atypical phenotypes and the use of indirect testing. The majority of cases with detectable mutations had a childhood onset but most are now adults, reflecting the long delay in diagnosis. The highest detection rate was in those with an adolescent onset and a family history (75%). The overall detection rate in our heterogeneous cohort was 18% and varied from 8.3% in those with an adult onset progressive disorder to 40% in those with a childhood or adolescent onset progressive disorder. Pathogenicity was assessed using a bioinformatics pipeline and novel variants were validated using functional experiments. In those cases where we identified the genetic mutation, we determined the time to diagnosis. All cases had been tested for spinocerebellar ataxia 1–3, 6, 7 and Friedrich’s ataxia and had multiple other biochemical, genetic and invasive tests. We captured 58 known human ataxia genes followed by Illumina Next-Generation Sequencing in 50 highly heterogeneous patients with ataxia who had been extensively investigated and were refractory to diagnosis. We performed a pilot study using heterogeneous ataxias as a model neurogenetic disorder to assess the introduction of next-generation sequencing into clinical practice. The advent of massively parallel, next-generation sequencing promises to revolutionize genetic testing and shorten the ‘diagnostic odyssey’ for many of these patients. The diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investigations without ever reaching a conclusive molecular diagnosis. Many neurological conditions are caused by immensely heterogeneous gene mutations.
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