Figure 1

Workflow of PhenoVar. PhenoVar automatically prioritizes diagnoses for validation based on both the phenotypic and genomic information of a proband. It calculates a patient-specific diagnostic score for each OMIM entry with known molecular basis. The diagnostic score assigned to a given syndrome is the sum of its phenotypic and genotypic weight. For each syndrome listed in the HPO database the phenotypic weight is determined by calculating the similarity between the proband and the different patients available in a local database (Phenobase). Phenobase includes simulated patients using HPO and real patients (here denoted as “local patients”). The genotypic weight for each syndrome corresponds to the (predicted) pathogenicity of any variants present in the proband’s exome specifically in the gene(s) causing the respective syndrome. When no variation is found in these genes, the genotypic weight for that syndrome is automatically set to null value. Otherwise, the variants are sorted into known disease-causing variants (DC var) versus possibly pathogenic variants (other var) and assigned a different score. The genotypic weight and phenotypic weight described above are summed to obtain the diagnostic score for each syndrome. The different syndromes are then ranked according to their diagnostic score.