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Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

Beryl B Cummings, Jamie L Marshall, Taru Tukiainen, Monkol Lek, Sandra Donkervoort, Reghan A. Foley, Veronique Bolduc, Leigh Waddell, Sarah Sandaradura, Gina O'Grady, Elicia Estrella, Hemakumar M Reddy, Fengmei Zhao, Ben Weisburd, Konrad J Karczewski, Anne O’Donnell-Luria, Daniel Birnbaum, Anna Sarkozy, Ying Hu, Hernan Gonorazky, Kristl Claeys, Himanshu Joshi, Adam Bournazos, Emily Oates, Roula Ghaoui, Mark Davis, Nigel Laing, Ana Topf, GTEx Consortium, Peter Kang, Alan Beggs, Kathryn N North, Volker Straub, James Dowling, Francesco Muntoni, Nigel F Clarke, Sandra T Cooper, Carsten G Bonnemann, Daniel G MacArthur
doi: https://doi.org/10.1101/074153
Beryl B Cummings
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA
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Jamie L Marshall
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Taru Tukiainen
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Monkol Lek
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Sandra Donkervoort
6Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, Maryland, USA
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Reghan A. Foley
6Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, Maryland, USA
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Veronique Bolduc
6Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, Maryland, USA
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Leigh Waddell
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Sarah Sandaradura
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Gina O'Grady
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Elicia Estrella
7Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA
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Hemakumar M Reddy
7Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA
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Fengmei Zhao
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Ben Weisburd
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Konrad J Karczewski
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Anne O’Donnell-Luria
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Daniel Birnbaum
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Anna Sarkozy
8Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK
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Ying Hu
6Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, Maryland, USA
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Hernan Gonorazky
9Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada
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Kristl Claeys
10Department of Neurology, University Hospitals Leuven and University of Leuven (KU Leuven), Leuven, Belgium
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Himanshu Joshi
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Adam Bournazos
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Emily Oates
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Roula Ghaoui
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Mark Davis
11Department of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Australia
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Nigel Laing
11Department of Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Australia
12Harry Perkins Institute of Medical Research, University of Western Australia, Perth, Australia
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Ana Topf
13The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
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Peter Kang
7Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA
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Alan Beggs
14Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA
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Kathryn N North
15Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Australia
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Volker Straub
13The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
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James Dowling
9Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada
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Francesco Muntoni
8Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK
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Nigel F Clarke
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Sandra T Cooper
4School of Paediatrics and Child Health, University of Sydney, Sydney, Australia
5Institute for Neuroscience and Muscle Research, Kids Research Institute, The Children's Hospital at Westmead, Sydney, Australia.
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Carsten G Bonnemann
6Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke/National Institutes of Health, Bethesda, Maryland, USA
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Daniel G MacArthur
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
2Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Abstract

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 25-50% [1–4]. Here, we explore the utility of transcriptome sequencing (RNA-seq) as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare neuromuscular 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 over 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 collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents the largest systematic application of transcriptome sequencing to rare disease diagnosis to date and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.

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Posted September 09, 2016.
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Improving genetic diagnosis in Mendelian disease with transcriptome sequencing
Beryl B Cummings, Jamie L Marshall, Taru Tukiainen, Monkol Lek, Sandra Donkervoort, Reghan A. Foley, Veronique Bolduc, Leigh Waddell, Sarah Sandaradura, Gina O'Grady, Elicia Estrella, Hemakumar M Reddy, Fengmei Zhao, Ben Weisburd, Konrad J Karczewski, Anne O’Donnell-Luria, Daniel Birnbaum, Anna Sarkozy, Ying Hu, Hernan Gonorazky, Kristl Claeys, Himanshu Joshi, Adam Bournazos, Emily Oates, Roula Ghaoui, Mark Davis, Nigel Laing, Ana Topf, GTEx Consortium, Peter Kang, Alan Beggs, Kathryn N North, Volker Straub, James Dowling, Francesco Muntoni, Nigel F Clarke, Sandra T Cooper, Carsten G Bonnemann, Daniel G MacArthur
bioRxiv 074153; doi: https://doi.org/10.1101/074153
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Improving genetic diagnosis in Mendelian disease with transcriptome sequencing
Beryl B Cummings, Jamie L Marshall, Taru Tukiainen, Monkol Lek, Sandra Donkervoort, Reghan A. Foley, Veronique Bolduc, Leigh Waddell, Sarah Sandaradura, Gina O'Grady, Elicia Estrella, Hemakumar M Reddy, Fengmei Zhao, Ben Weisburd, Konrad J Karczewski, Anne O’Donnell-Luria, Daniel Birnbaum, Anna Sarkozy, Ying Hu, Hernan Gonorazky, Kristl Claeys, Himanshu Joshi, Adam Bournazos, Emily Oates, Roula Ghaoui, Mark Davis, Nigel Laing, Ana Topf, GTEx Consortium, Peter Kang, Alan Beggs, Kathryn N North, Volker Straub, James Dowling, Francesco Muntoni, Nigel F Clarke, Sandra T Cooper, Carsten G Bonnemann, Daniel G MacArthur
bioRxiv 074153; doi: https://doi.org/10.1101/074153

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