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December 2018

Need for Automated Interactive Genomic Interpretation and Ongoing Reanalysis

Author Affiliations
  • 1Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 2Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 3Department of Genetics, Al Jalila Children’s Specialty Hospital, Dubai, United Arab Emirates
JAMA Pediatr. 2018;172(12):1113-1114. doi:10.1001/jamapediatrics.2018.2675

Traditional genetic testing was based on Sanger sequencing analysis of a single gene at a time. A clinician would generate a differential diagnosis after synthesizing the patient’s history, physical examination findings, metabolic test results, and imaging studies and then would send for sequencing of the gene that is most commonly associated with the phenotype. If this test had negative results, the clinician often progressed to testing for other genes possibly associated with the phenotype. This candidate gene approach to genetic testing was stymied by genetic heterogeneity, atypical presentations (variable expressivity and reduced penetrance), poorly delineated clinical features, and the presence of ultrarare disorders in the differential diagnosis. Approximately half of individuals with a genetic disorder never received an accurate diagnosis, and the diagnosis was often significantly delayed for those who did.1