Fig. 10

EvORanker identifies DLGAP2 as a novel gene underlying a neurodevelopmental phenotype. A Pedigree: In a consanguineous family affected children have psychomotor delay and dysphasia, hyperactivity, and poor attention span. Shown is the segregation of the DLGAP2 NM_001346810:c.A2702T, p.Glu901Val variant. N, normal allele; V, variant allele. B EvORanker results: DLGAP2 is ranked as the top candidate relative to the other patient candidates. The x-axis indicates the proband (patient II-3), and the y-axis indicates the EvORanker -log(10) p-value obtained from running the K-S test using the co-evolved and STRING-interacting genes with each patient gene. Red dots indicate significant p-values, and dark blue dots indicate non-significant p-values. DLGAP2 was the only gene that co-segregated with the phenotype in family 1. C One-sided, two-sample Kolmogorov–Smirnov model. The x-axis indicates the semantic similarity score obtained by the OntologySimilarity tool in relation to the patient’s (II-3, family 1) phenotypes (HP:0001263, HP:0002357, HP:0000752, HP:0000736). The y-axis indicates the cumulative distribution. The orange line corresponds to the empirical distribution of all genes listed in the HPO database, ranked according to semantic similarity. The red line represents the empirical distribution of the genes coevolved with DLGAP2, and the blue line represents the empirical distribution of the genes interacting with DLGAP2 based on STRING. The red dashed line indicates the D statistic representing the maximum vertical distance between the empirical cumulative distribution functions of the HPO-ranked genes and the genes coevolved with DLGAP2. The blue dashed line indicates the D statistic measured by the distance between the empirical cumulative distribution functions of the HPO-ranked genes and the genes interacting with DLGAP2 based on STRING. Both coevolution and STRING-based analysis yielded significant p-values corresponding to the D statistic. D Coevolution and STRING-based subnetwork showing the patient’s phenotype-related genes coevolving with the DLGAP2 gene. The dark grey node in the network indicates DLGAP2 and the light grey nodes represent the phenotype-related genes. The black edges represent STRING interactions, and the colored edges represent the clade where two genes co-evolve. The network exhibits a group of phenotype-related correlated genes that have not been identified by the STRING database (EHMT1, IL1RAPL1, SATB2, GABRA5, SRPX2, SEMA3E, CACNG2)