1. Improving the diagnostic yield of exome-sequencing, by predicting gene-phenotype associations using large-scale gene expression analysis
- Author
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Sabrina Z. Jan, Wilhelmina S. Kerstjens-Frederikse, Morris A. Swertz, Pytrik Folkertsma, Peter C. van den Akker, K. Joeri van der Velde, Roan Kanninga, Johanna C. Herkert, Jan D. H. Jongbloed, Edgar T. Hoorntje, Richard J. Sinke, Lude Franke, Patrick Deelen, Erica H. Gerkes, Harm Brugge, Yvonne J. Vos, Sipko van Dam, Kristin M. Abbott, Tessa Gillett, Birgit Sikkema-Raddatz, Conny M. A. van Ravenswaaij-Arts, Cleo C. van Diemen, Paul A. van der Zwaag, Juha Karjalainen, and Wouter P. te Rijdt
- Subjects
0303 health sciences ,Candidate gene ,Causative gene ,Computational biology ,Biology ,Phenotype ,DNA sequencing ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Gene ,Exome ,030217 neurology & neurosurgery ,Exome sequencing ,030304 developmental biology - Abstract
Clinical interpretation of exome and genome sequencing data remains challenging and time consuming, with many variants with unknown effects found in genes with unknown functions. Automated prioritization of these variants can improve the speed of current diagnostics and identify previously unknown disease genes. Here, we used 31,499 RNA-seq samples to predict the phenotypic consequences of variants in genes. We developed GeneNetwork Assisted Diagnostic Optimization (GADO), a tool that uses these predictions in combination with a patient’s phenotype, denoted using HPO terms, to prioritize identified variants and ease interpretation. GADO is unique because it does not rely on existing knowledge of a gene and can therefore prioritize variants missed by tools that rely on existing annotations or pathway membership. In a validation trial on patients with a known genetic diagnosis, GADO prioritized the causative gene within the top 3 for 41% of the cases. Applying GADO to a cohort of 38 patients without genetic diagnosis, yielded new candidate genes for seven cases. Our results highlight the added value of GADO (www.genenetwork.nl) for increasing diagnostic yield and for implicating previously unknown disease-causing genes.
- Published
- 2018
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