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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts.
Frésard, Laure; Smail, Craig; Ferraro, Nicole M; Teran, Nicole A; Li, Xin; Smith, Kevin S; Bonner, Devon; Kernohan, Kristin D; Marwaha, Shruti; Zappala, Zachary; Balliu, Brunilda; Davis, Joe R; Liu, Boxiang; Prybol, Cameron J; Kohler, Jennefer N; Zastrow, Diane B; Reuter, Chloe M; Fisk, Dianna G; Grove, Megan E; Davidson, Jean M; Hartley, Taila; Joshi, Ruchi; Strober, Benjamin J; Utiramerur, Sowmithri; Lind, Lars; Ingelsson, Erik; Battle, Alexis; Bejerano, Gill; Bernstein, Jonathan A; Ashley, Euan A; Boycott, Kym M; Merker, Jason D; Wheeler, Matthew T; Montgomery, Stephen B.
Affiliation
  • Frésard L; Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA. lfresard@stanford.edu.
  • Smail C; Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
  • Ferraro NM; Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
  • Teran NA; Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
  • Li X; Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Smith KS; Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Bonner D; Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
  • Kernohan KD; Newborn Screening Ontario (NSO), Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
  • Marwaha S; Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
  • Zappala Z; Stanford Cardiovascular Institute, School of Medicine, Stanford University, Stanford, CA, USA.
  • Balliu B; Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
  • Davis JR; Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Liu B; Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
  • Prybol CJ; Department of Biology, School of Humanities and Sciences, Stanford University, Stanford, CA, USA.
  • Kohler JN; Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
  • Zastrow DB; Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
  • Reuter CM; Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
  • Fisk DG; Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
  • Grove ME; Stanford Medicine Clinical Genomics Program, School of Medicine, Stanford University, Stanford, CA, USA.
  • Davidson JM; Stanford Medicine Clinical Genomics Program, School of Medicine, Stanford University, Stanford, CA, USA.
  • Hartley T; Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
  • Joshi R; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
  • Strober BJ; Stanford Medicine Clinical Genomics Program, School of Medicine, Stanford University, Stanford, CA, USA.
  • Utiramerur S; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Ingelsson E; Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
  • Battle A; Stanford Cardiovascular Institute, School of Medicine, Stanford University, Stanford, CA, USA.
  • Bejerano G; Department of Medicine, Division of Cardiovascular Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
  • Bernstein JA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Ashley EA; Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.
  • Boycott KM; Department of Computer Science, Stanford University, Stanford, CA, USA.
  • Merker JD; Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA, USA.
  • Wheeler MT; Department of Developmental Biology, School of Medicine, Stanford University, Stanford, CA, USA.
  • Montgomery SB; Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA.
Nat Med ; 25(6): 911-919, 2019 06.
Article in En | MEDLINE | ID: mdl-31160820
ABSTRACT
It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Rare Diseases Type of study: Diagnostic_studies / Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Child / Child, preschool / Female / Humans / Male Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2019 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Rare Diseases Type of study: Diagnostic_studies / Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Child / Child, preschool / Female / Humans / Male Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2019 Document type: Article Affiliation country: Estados Unidos