Abstract
PhenomeNet is an approach for integrating phenotypes across species and identifying candidate genes for genetic diseases based on the similarity between a disease and animal model phenotypes. In contrast to ‘guilt-by-association’ approaches, PhenomeNet relies exclusively on the comparison of phenotypes to suggest candidate genes, and can, therefore, be applied to study the molecular basis of rare and orphan diseases for which the molecular basis is unknown. In addition to disease phenotypes from the Online Mendelian Inheritance in Man (OMIM) database, we have now integrated the clinical signs from Orphanet into PhenomeNet. We demonstrate that our approach can efficiently identify known candidate genes for genetic diseases in Orphanet and OMIM. Furthermore, we find evidence that mutations in the HIP1 gene might cause Bassoe syndrome, a rare disorder with unknown genetic aetiology. Our results demonstrate that integration and computational analysis of human disease and animal model phenotypes using PhenomeNet has the potential to reveal novel insights into the pathobiology underlying genetic diseases.
Highlights
Two major goals of biomedical research are the in-depth understanding of the function of genes and their role in human disease
Based on the similarity between phenotypic manifestations observed in mutant mice and the clinical signs associated with disorders in Orphanet, we present and discuss evidence that the Huntingtin-interacting protein 1 (HIP1) gene may be responsible for Bassoe syndrome
Our results demonstrate that integration and computational analysis of human disease and animal model phenotypes using PhenomeNet has the potential to reveal novel insights into the pathobiology underlying genetic diseases
Summary
Two major goals of biomedical research are the in-depth understanding of the function of genes and their role in human disease. In addition to hypothesis-based studies, systematic mutagenesis and phenotyping programmes are being implemented for several model organisms, with the aim of describing the phenotypes associated with mutations in every proteincoding gene, revealing the genes’ functions, the structure and dynamics of physiological pathways as well as providing insights into the pathobiology of disease. While the manifestations of mutations in homologous genes might be expected to give rather diverse phenotypes in different organisms, it has been shown that in many cases, between vertebrates, phenotypes are remarkably conserved, implying that the underlying physiological pathways in which these genes function are themselves highly conserved. Animal models are a valuable tool for the investigation of gene function and the study of human disease
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