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October 2014

Clinical Exome Sequencing: The New Standard in Genetic Diagnosis

Author Affiliations
  • 1Department of Neurology, University of Chicago, Chicago, Illinois
  • 2Department of Human Genetics, University of Chicago, Chicago, Illinois
JAMA Neurol. 2014;71(10):1215-1216. doi:10.1001/jamaneurol.2014.2015

Clinical exome sequencing has arrived and likely is here to stay for the foreseeable future as a key component of routine diagnostic evaluations. When applied to a condition as genetically heterogeneous as the ataxias, it is likely to prove fruitful to yield a molecular diagnosis. The article by Fogel et al1 is the third and most extensive to apply this method for a diagnostic evaluation in the ataxias.2,3 The present study made a definitive genetic diagnosis in 21% of 76 consecutive patients with ataxia after excluding repeat expansion disorders and identified probable/suspicious variants in an additional 40%. This is an impressive result considering previous studies selected for patients with childhood onset or multiplex families. These results are similar to those of other prospective exome sequencing studies—one in which 115 consecutive patients with diverse conditions, ranging from developmental delay or birth defects to cardiomyopathy, deafness, or skeletal dysplasia, were subjected to exome sequencing4 and another study of 250 patients with diverse, predominantly neurologic phenotypes.5 Although the criteria for making a determination of a definitive genetic diagnosis based on these results are not spelled out in the former study, the authors were able to make a genetic diagnosis in 37% of those cases, while in the latter study, 25% achieved genetic diagnosis. In general, the growing number of reported exome sequence studies demonstrates that this technology is now increasingly available as a diagnostic option.2-4 The present ataxia exome sequencing study is notable for the higher proportion of adult-onset cases and sporadic cases identified, suggesting a broader use than previous reports.1