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

• Published in: Nature communications 2019-06, Vol.10 (1), p.2837-13, Article 2837
• Main Authors: Deelen, Patrick, van Dam, Sipko, Herkert, Johanna C., Karjalainen, Juha M., Brugge, Harm, Abbott, Kristin M., van Diemen, Cleo C., van der Zwaag, Paul A., Gerkes, Erica H., Zonneveld-Huijssoon, Evelien, Boer-Bergsma, Jelkje J., Folkertsma, Pytrik, Gillett, Tessa, van der Velde, K. Joeri, Kanninga, Roan, van den Akker, Peter C., Jan, Sabrina Z., Hoorntje, Edgar T., te Rijdt, Wouter P., Vos, Yvonne J., Jongbloed, Jan D. H., van Ravenswaaij-Arts, Conny M. A., Sinke, Richard, Sikkema-Raddatz, Birgit, Kerstjens-Frederikse, Wilhelmina S., Swertz, Morris A., Franke, Lude
• Format: Article
• Language: English
• Subjects: 38/91; 45/23; 631/114/2401; 631/114/2410; 631/208/1516; 692/700/139/1512; Databases, Nucleic Acid; Diagnostic systems; Gene expression; Gene Expression Regulation - physiology; Gene sequencing; Genes; Genetic Predisposition to Disease; Genetic screening; Genomes; Humanities and Social Sciences; Humans; Models, Genetic; multidisciplinary; Optimization; Phenotypes; Principal Component Analysis; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sequence Analysis, RNA - methods; Software; Transcriptome; User-Computer Interface
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10649-4

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 www.genenetwork.nl 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. A genetic diagnosis remains unattainable for many individuals with a rare disease because of incomplete knowledge about the genetic basis of many diseases. Here, the authors present the web-based tool GADO (GeneNetwork Assisted Diagnostic Optimization) that uses public RNA-seq data for prioritization of candidate genes.