DIAPH1 is a candidate gene for macrothrombocytopenia and hearing loss. (A) Each BPD index case was coded using HPO terms relating to hematologic features and to phenotypes in other organ systems and underwent high-throughput sequencing.¹⁸  Candidate genes for BPD were identified by similarity regression in which “baseline” and “alternate” statistical models are compared for every gene.¹⁹  Under the baseline model, all cases are assumed to have the same log odds of carrying a rare variant. Under the alternate model, which we give a prior probability of .05 of being the true model, the log odds is modeled as a linear function of the phenotypic similarity of each case to an HPO-encoded “characteristic phenotype.” The characteristic phenotype (φ) and a binary variable indicating the true model (γ) are inferred from the genotype and phenotype data. A high posterior mean for γ is indicative of a potential association between the presence of a rare variant in a gene, coded by a binary vector y, and a disorder characterized by φ. The histogram indicates the mean posterior probability of the alternate model being true (P(γ = 1|y)) for all 1073 genes in which at least 2 BPD cases carry a high-impact variant. The value for DIAPH1 is indicated in red. (B) The inferred HPO-coded characteristic phenotype (φ) for DIAPH1 is represented as a graph, whereby each edge denotes an “is a” relationship and each node contains an HPO term with its marginal posterior probability of inclusion in φ, which is also represented by the node size. When a node and all its descendants in the HPO graph have a marginal posterior probability of inclusion in φ <0.02, it is not shown. (C) Pedigrees of the index cases (*) in which the colored symbols indicate macrothrombocytopenia (black) and hearing loss (red). The gray symbols indicate that the clinical phenotype is unknown, and the white symbols indicate no macrothrombocytopenia or hearing loss. Genotyped cases are indicated by +/M for the heterozygous DIAPH1 R1213* variant and by +/+ for the reference sequence at that locus. BBFT, Abnormality of blood and blood forming tissues; Bleeding, Abnormal bleeding; Ear, Abnormality of the ear; FAIE, Functional abnormality of the inner ear; Inner ear, Abnormality of the inner ear; Platelet count, Abnormal platelet count; SNHI, Sensorineural hearing impairment; Thrombocytes, Abnormality of thrombocytes; TCP, Thrombocytopenia.