Improving the diagnostic yield of exome-sequencing by predicting gene-phenotype associations using large-scale gene expression analysis

Patrick Deelen, Sipko van Dam, Johanna C Herkert, Juha M Karjalainen, Harm Brugge, Kristin M Abbott, Cleo C van Diemen, Paul A van der Zwaag, Erica H Gerkes, Evelien Zonneveld-Huijssoon, Jelkje J Boer-Bergsma, Pytrik Folkertsma, Tessa Gillett, K Joeri van der Velde, Roan Kanninga, Peter C van den Akker, Sabrina Z Jan, Edgar T Hoorntje, Wouter P Te Rijdt, Yvonne J VosJan D H Jongbloed, Conny M A van Ravenswaaij-Arts, Richard Sinke, Birgit Sikkema-Raddatz, Wilhelmina S Kerstjens-Frederikse, Morris A Swertz, Lude Franke

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The diagnostic yield of exome and genome sequencing remains low (8-70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases.

Original languageEnglish
Article number2837
Number of pages13
JournalNature Communications
Issue number1
Publication statusPublished - 28-Jun-2019



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