Abstract
BackgroundMutations of different genes often result in clinically similar diseases. Among the datasets of similar diseases, we analyzed the ‘phenotypic series’ from Online Mendelian Inheritance in Man and examined the similarity of the diseases that belong to the same phenotypic series, because we hypothesize that clinical similarity may unveil shared pathogenic mechanisms.MethodsSpecifically, for each pair of diseases, we quantified their similarity, based on both number and information content of the shared clinical phenotypes. Then, we assembled the disease similarity network, in which nodes represent diseases and edges represent clinical similarities.ResultsOn average, diseases have high similarity with other diseases of their own phenotypic series, even though about one third of diseases have their maximal similarity with a disease of another series. Consequently, the network is assortative (i.e., diseases belonging to the same series link preferentially to each other), but the series differ in the way they distribute within the network. Specifically, heterophobic series, which minimize links to other series, form islands at the periphery of the network, whereas heterophilic series, which are highly inter-connected with other series, occupy the center of the network.ConclusionsThe finding that the phenotypic series display not only internal similarity (assortativity) but also varying degrees of external similarity (ranging from heterophobicity to heterophilicity) calls for investigation of biological mechanisms that might be shared among different series. The correlation between the clinical and biological similarities of the phenotypic series is analyzed in Part II of this study1.
Highlights
Mutations of different genes often result in clinically similar diseases
We expected that pairs of D, which belong to the same Phenotypic Series (PS), have high similarity scores and are linked in the Disease-disease similarity network-clinical (DDSN-C), such that the PS emerge as dyadic properties
We expected that pairs of D, which belong to different PS, have low similarity scores and are not linked in the DDSN-C
Summary
Mutations of different genes often result in clinically similar diseases. After the early reports of gene mutations as causes of inherited diseases (D), the ‘one gene-one disease’ paradigm became widely accepted. A mutation in one gene results in the production of a dysfunctional disease gene product (DGP), in general a protein, which in turn (in a direct or indirect way) causes the disease phenotypes (DP) that characterize the D [1]. In locus heterogeneity, mutations in different (and often seemingly unrelated) genes cause similar (if not identical) D [2]. The mutations of different genes, which cause clinically similar D, could be thought of as
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