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Improving the diagnostic yield of exome- sequencing by predicting gene-phenotype associations using large-scale gene expression analysis.
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.
Affiliation
  • Deelen P; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • van Dam S; University of Groningen, University Medical Center Groningen, Genomics Coordination Center, 9700 VB, Groningen, The Netherlands.
  • Herkert JC; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Karjalainen JM; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Brugge H; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Abbott KM; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • van Diemen CC; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • van der Zwaag PA; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Gerkes EH; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Zonneveld-Huijssoon E; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Boer-Bergsma JJ; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Folkertsma P; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Gillett T; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • van der Velde KJ; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Kanninga R; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • van den Akker PC; University of Groningen, University Medical Center Groningen, Genomics Coordination Center, 9700 VB, Groningen, The Netherlands.
  • Jan SZ; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Hoorntje ET; University of Groningen, University Medical Center Groningen, Genomics Coordination Center, 9700 VB, Groningen, The Netherlands.
  • Te Rijdt WP; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Vos YJ; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Jongbloed JDH; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • van Ravenswaaij-Arts CMA; Netherlands Heart Institute, 3511 EP, Utrecht, The Netherlands.
  • Sinke R; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Sikkema-Raddatz B; Netherlands Heart Institute, 3511 EP, Utrecht, The Netherlands.
  • Kerstjens-Frederikse WS; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Swertz MA; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
  • Franke L; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.
Nat Commun ; 10(1): 2837, 2019 06 28.
Article in En | MEDLINE | ID: mdl-31253775
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gene Expression Regulation / Sequence Analysis, RNA / Genetic Predisposition to Disease / Transcriptome Type of study: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2019 Document type: Article Affiliation country: Netherlands
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gene Expression Regulation / Sequence Analysis, RNA / Genetic Predisposition to Disease / Transcriptome Type of study: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2019 Document type: Article Affiliation country: Netherlands