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
Sarmady M, Abou Tayoun A. Need for Automated Interactive Genomic Interpretation and Ongoing Reanalysis. JAMA Pediatr. 2018;172(12):1113–1114. doi:10.1001/jamapediatrics.2018.2675
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