Fig. 1

Integration of phenotype with genotype in clinical diagnostics of genetic disease. a The diagnostic process is informed by both phenotype and genotype data to arrive at diagnostic conclusions. During the clinical evaluation of patients with suspected genetic disease, physicians observe phenotypic features, and these can be represented in controlled vocabularies (e.g., Human Phenotype Ontology, HPO), amenable to subsequent computational analysis. Physicians also request the acquisition of blood or other tissue samples for molecular characterization of the patient via genome-wide analyses, such as next-generation sequencing. Genotypic analysis provides high-resolution information concerning the location, type, and zygosity of variants within the patient genome. Integration of these data identifies possible solutions that simultaneously match both phenotype and genotype of the patient, excluding unlikely diagnostic candidates and improving differential diagnosis. b Our transitive prioritization approach ranks genes and the variants they harbor against patient phenotype as a function of the discrete disease scores with which the genes were previously associated. This avoids potential underweighting and corresponding ranking inaccuracies resulting from the collapsing approach or direct term-to-gene HPO annotations. c We implemented a curatorial and visual transitive closure approach to infer phenotypic prioritization scores for patient genotype variants. These scores are based on clinical indication similarity scores computed for diseases in the catalog that are reportedly caused by variants in genes that contain filtered patient variants. When multiple diseases are cataloged to result from variants in the same gene, we determine the gene’s score by aggregation of the scores of those diseases using an integrative function. Variants then inherit the scores of the genes in which they are located. The manual curatorial exclusion of diseases or genes from consideration for diagnosis transitively propagates to eliminate genes and variants from the differential