Introduction

Clinical evaluation of CNVs identified via techniques such as array comparative genome hybridisation (aCGH) involves the inspection of lists of known and unknown duplications and deletions with the goal of distinguishing pathogenic from benign CNVs. A key step in this process is the comparison of the individual's phenotypic abnormalities with those associated with Mendelian disorders of the genes affected by the CNV. However, because often there is not much known about these human genes, an additional source of data that could be used is model organism phenotype data. Currently, almost 6000 genes in mouse and zebrafish are, when knocked out, associated with a phenotype in the model organism, but no disease is known to be caused by mutations in the human ortholog. Yet, searching model organism databases and comparing model organism phenotypes with patient phenotypes for identifying novel disease genes and medical evaluation of CNVs is hindered by the difficulty in integrating phenotype information across species and the lack of appropriate software tools.Here, we present an integrated ranking scheme based on phenotypic matching, degree of overlap with known benign or pathogenic CNVs and the haploinsufficiency score for the prioritisation of CNVs responsible for a patient's clinical findings.We show that this scheme leads to significant improvements compared with rankings that do not exploit phenotypic information. We provide a software tool called PhenogramViz, which supports phenotype-driven interpretation of aCGH findings based on multiple data sources, including the integrated cross-species phenotype ontology Uberpheno, in order to visualise gene-to-phenotype relations.Integrating and visualising cross-species phenotype information on the affected genes may help in routine diagnostics of CNVs.

Publications

  1. Clinical interpretation of CNVs with cross-species phenotype data.
    Cite this
    Köhler S, Schoeneberg U, Czeschik JC, Doelken SC, Hehir-Kwa JY, Ibn-Salem J, Mungall CJ, Smedley D, Haendel MA, Robinson PN, 2014-11-01 - Journal of medical genetics

Credits

  1. Sebastian Köhler
    Developer

    Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany

  2. Uwe Schoeneberg
    Developer

    Foundation Institute Molecular Biology and Bioinformatics, Freie Universitaet Berlin, Germany

  3. Johanna Christina Czeschik
    Developer

    Institut für Humangenetik, Universitätsklinikum Essen, Germany

  4. Sandra C Doelken
    Developer

    Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Germany

  5. Jayne Y Hehir-Kwa
    Developer

    Department of Human Genetics, Radboud University Medical Centre

  6. Jonas Ibn-Salem
    Developer

    Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Germany

  7. Christopher J Mungall
    Developer

    Lawrence Berkeley National Laboratory, Berkeley, United States of America

  8. Damian Smedley
    Developer

    The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus

  9. Melissa A Haendel
    Developer

    Department of Medical Informatics and Epidemiology and OHSU Library, Oregon Health & Science University, United States of America

  10. Peter N Robinson
    Investigator

    Department of Mathematics and Computer Science, Institute for Bioinformatics, Germany

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Summary
AccessionBT006577
Tool TypeApplication
Category
PlatformsLinux/Unix
Technologies
User InterfaceTerminal Command Line
Download Count0
Country/RegionGermany
Submitted ByPeter N Robinson