Exome Sequencing Identifies New Disease Phenotypes in Characterized Genes.

A major benefit of diagnostic exome sequencing (DES) is the simultaneous interrogation of virtually all genes, both characterized and uncharacterized as well as genes that are both related to and outside of the clinician’s differential diagnoses. This unbiased and assumption-free approach enables opportunities for novel candidate gene discovery, finer delineation of genotype-phenotype correlations, as well as new disease discovery among already characterized genes. Overall, DES is successful in ending the diagnostic odyssey for 30% of undiagnosed patients with underlying Mendelian disorders in characterized genes. Additionally, a novel candidate gene-disease relationship is identified among ~8% of patients in whom uncharacterized genes are analyzed. DES has expanded phenotypes within genes with well-established disease associations and in a subset of cases these broader phenotypes are distinct enough from the already-established diseases to be considered novel gene-disease associations.