Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.

نویسندگان

  • Beryl B Cummings
  • Jamie L Marshall
  • Taru Tukiainen
  • Monkol Lek
  • Sandra Donkervoort
  • A Reghan Foley
  • Veronique Bolduc
  • Leigh B Waddell
  • Sarah A Sandaradura
  • Gina L O'Grady
  • Elicia Estrella
  • Hemakumar M Reddy
  • Fengmei Zhao
  • Ben Weisburd
  • Konrad J Karczewski
  • Anne H O'Donnell-Luria
  • Daniel Birnbaum
  • Anna Sarkozy
  • Ying Hu
  • Hernan Gonorazky
  • Kristl Claeys
  • Himanshu Joshi
  • Adam Bournazos
  • Emily C Oates
  • Roula Ghaoui
  • Mark R Davis
  • Nigel G Laing
  • Ana Topf
  • Peter B Kang
  • Alan H Beggs
  • Kathryn N North
  • Volker Straub
  • James J Dowling
  • Francesco Muntoni
  • Nigel F Clarke
  • Sandra T Cooper
  • Carsten G Bönnemann
  • Daniel G MacArthur
چکیده

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.

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عنوان ژورنال:
  • Science translational medicine

دوره 9 386  شماره 

صفحات  -

تاریخ انتشار 2017