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Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.
Lee, Hane; Huang, Alden Y; Wang, Lee-Kai; Yoon, Amanda J; Renteria, Genecee; Eskin, Ascia; Signer, Rebecca H; Dorrani, Naghmeh; Nieves-Rodriguez, Shirley; Wan, Jijun; Douine, Emilie D; Woods, Jeremy D; Dell'Angelica, Esteban C; Fogel, Brent L; Martin, Martin G; Butte, Manish J; Parker, Neil H; Wang, Richard T; Shieh, Perry B; Wong, Derek A; Gallant, Natalie; Singh, Kathryn E; Tavyev Asher, Y Jane; Sinsheimer, Janet S; Krakow, Deborah; Loo, Sandra K; Allard, Patrick; Papp, Jeanette C; Palmer, Christina G S; Martinez-Agosto, Julian A; Nelson, Stanley F.
Afiliación
  • Lee H; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Huang AY; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Wang LK; Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Yoon AJ; Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Renteria G; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Eskin A; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Signer RH; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Dorrani N; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Nieves-Rodriguez S; Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Wan J; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Douine ED; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Woods JD; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Dell'Angelica EC; Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Fogel BL; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Martin MG; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Butte MJ; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Parker NH; Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Wang RT; Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Shieh PB; Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA, USA.
  • Wong DA; Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Gallant N; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Singh KE; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Tavyev Asher YJ; Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Sinsheimer JS; Department of Pediatrics, School of Medicine, University of California-Irvine, Irvine, CA, USA.
  • Krakow D; Miller Children's and Women's Hospital, Long Beach, CA, USA.
  • Loo SK; Department of Pediatrics, School of Medicine, University of California-Irvine, Irvine, CA, USA.
  • Allard P; Miller Children's and Women's Hospital, Long Beach, CA, USA.
  • Papp JC; Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Palmer CGS; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Martinez-Agosto JA; Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
  • Nelson SF; Department of Biomathematics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Genet Med ; 22(3): 490-499, 2020 03.
Article en En | MEDLINE | ID: mdl-31607746
ABSTRACT

PURPOSE:

We investigated the value of transcriptome sequencing (RNAseq) in ascertaining the consequence of DNA variants on RNA transcripts to improve the diagnostic rate from exome or genome sequencing for undiagnosed Mendelian diseases spanning a wide spectrum of clinical indications.

METHODS:

From 234 subjects referred to the Undiagnosed Diseases Network, University of California-Los Angeles clinical site between July 2014 and August 2018, 113 were enrolled for high likelihood of having rare undiagnosed, suspected genetic conditions despite thorough prior clinical evaluation. Exome or genome sequencing and RNAseq were performed, and RNAseq data was integrated with genome sequencing data for DNA variant interpretation genome-wide.

RESULTS:

The molecular diagnostic rate by exome or genome sequencing was 31%. Integration of RNAseq with genome sequencing resulted in an additional seven cases with clear diagnosis of a known genetic disease. Thus, the overall molecular diagnostic rate was 38%, and 18% of all genetic diagnoses returned required RNAseq to determine variant causality.

CONCLUSION:

In this rare disease cohort with a wide spectrum of undiagnosed, suspected genetic conditions, RNAseq analysis increased the molecular diagnostic rate above that possible with genome sequencing analysis alone even without availability of the most appropriate tissue type to assess.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedades Raras / Patología Molecular / Transcriptoma / Enfermedades Genéticas Congénitas Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Humans Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedades Raras / Patología Molecular / Transcriptoma / Enfermedades Genéticas Congénitas Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Humans Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos