Fig. 11

EvORanker identifies LPCAT3 as a novel gene underlying a multisystem disorder. A Pedigree of a consanguineous family. The affected son has failure to thrive, chronic diarrhea with recurrent abdominal pain, muscle atrophy, elevated liver enzymes, and high creatine kinase levels. Shown is the segregation of the LPCAT3 NM_005768:c.G939A, p.Trp313Ter variant. N, normal allele; V, variant allele. B EvORanker results: LPCAT3 is ranked as the top candidate relative to other candidate genes. The x-axis indicates the proband (patient II-4), and the y-axis indicates the combined -log10 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. LPCAT3 was the only gene that co-segregated with the phenotype in family 2. 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-4, family 2) phenotypes (HP:0001508, HP:0002910, HP:0002574, HP:0002028, HP:0003236, HP:0003202). 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 indicates the empirical distribution of the genes coevolved with LPCAT3, and the blue line indicates the empirical distribution of the genes interacting with LPCAT3 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 LPCAT3. 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 LPCAT3 based on STRING. Only coevolution-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 LPCAT3 gene. The yellow node in the network indicates LPCAT3 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. We demonstrate that our clade-wise NPP approach uncovered correlations between LPCAT3 and phenotype-related genes that were not captured by STRING