Phenotype-genotype comorbidity analysis of patients with rare disorders provides insight into their pathological and molecular bases

We present a computational approach that connects patient phenotypes based on phenotypic co-occurence and uses genomic information related to the patient mutations to assign genes to the phenotypes, which are us ed to detect enriched functional systems. These phenotypes are clustered using network analysis to obtain functionally coherent phenotype clusters. We applied the approach to the DECIPHER database, containing phenotypic and genomic information for thousands of patients with heterogeneous rare disord ers and copy number variants. Validity was demonstrated through overlap with known diseases, co-mention within the biomedical literature, semantic similarity measures, and patient cluster membership. These connected pairs formed multiple phenotype clusters, showing functional coherence, and mapped t o genes and systems involved in similar pathological processes. Examples include claudin genes from the 22q11 genomic region associated with a cluster of phenotypes related to DiGeorge syndrome and genes related to the GO term anterior/posterior pattern specification associated with abnormal develop ment. The clusters generated can help with the diagnosis of rare diseases, by suggesting additional phenotypes for a given patient and potential underlying functional systems. Other tools to find causal genes based on phenotype were also investigated. The approach has been implemented as a workflow, named PhenCo, which can be adapted to any set of patients for which phenomic and gen...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research