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Genetic diagnosis of Mendelian disorders via RNA sequencing

Laura S Kremer, View ORCID ProfileDaniel M Bader, Christian Mertes, Robert Kopajtich, Garwin Pichler, Arcangela Iuso, Tobias B Haack, Elisabeth Graf, Thomas Schwarzmayr, Caterina Terrile, Eliška Koňaříková, Birgit Repp, Gabi Kastenmüller, Jerzy Adamski, Peter Lichtner, Christoph Leonhardt, Benoit Funalot, Alice Donati, Valeria Tiranti, Anne Lombes, Claude Jardel, Dieter Gläser, Robert W. Taylor, Daniele Ghezzi, Johannes A Mayr, Agnes Rötig, Peter Freisinger, Felix Distelmaier, Tim M Strom, Thomas Meitinger, Julien Gagneur, Holger Prokisch
doi: https://doi.org/10.1101/066738
Laura S Kremer
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Daniel M Bader
3Department of Informatics, Technische Universität München, 85748 Garching, Germany
4Quantitative Biosciences Munich, Gene Center, Department of Biochemistry, Ludwig Maximilian Universität München, 81377 Munich, Germany
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  • ORCID record for Daniel M Bader
Christian Mertes
3Department of Informatics, Technische Universität München, 85748 Garching, Germany
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Robert Kopajtich
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Garwin Pichler
5Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany
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Arcangela Iuso
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Tobias B Haack
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Elisabeth Graf
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Thomas Schwarzmayr
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Caterina Terrile
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
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Eliška Koňaříková
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Birgit Repp
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Gabi Kastenmüller
6Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany
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Jerzy Adamski
7Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
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Peter Lichtner
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
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Christoph Leonhardt
8Neuropädiatrie, Neonatologie, 78050 Villingen-Schwenningen, Germany
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Benoit Funalot
9INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris,France
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Alice Donati
10Metabolic Unit, A. Meyer Children’s Hospital, Florence, Italy
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Valeria Tiranti
11Unit of Molecular Neurogenetics, Foundation IRCCS (Istituto di Ricovero e Cura a Carettere Scientifico) Neurological Institute “Carlo Besta”, 20126 Milan, Italy
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Anne Lombes
12Inserm UMR 1016, Institut Cochin, 75014 Paris, France
13CNRS UMR 8104, Institut Cochin, 75014 Paris, France
14Université Paris V René Descartes, Institut Cochin, 75014 Paris, France
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Claude Jardel
12Inserm UMR 1016, Institut Cochin, 75014 Paris, France
15AP/HP, GHU Pitié-Salpêtrière, Service de Biochimie Métabolique, 75013, Paris, France
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Dieter Gläser
16Genetikum, Genetic Counseling and Diagnostics, 89231 Neu-Ulm, Germany
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Robert W. Taylor
17Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
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Daniele Ghezzi
9INSERM U1163, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris,France
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Johannes A Mayr
18Department of Pediatrics, Paracelsus Medical University, A-5020 Salzburg, Austria
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Agnes Rötig
8Neuropädiatrie, Neonatologie, 78050 Villingen-Schwenningen, Germany
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Peter Freisinger
19Department of Pediatrics, Klinikum Reutlingen, 72764 Reutlingen, Germany
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Felix Distelmaier
20Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
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Tim M Strom
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Thomas Meitinger
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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Julien Gagneur
3Department of Informatics, Technische Universität München, 85748 Garching, Germany
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Holger Prokisch
1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
2Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München,, 81675 München, Germany
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  • For correspondence: prokisch@helmholtz-muenchen.de gagneur@in.tum.de
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Abstract

Across a large variety of Mendelian disorders, 50 to 75% of undiagnosed patients do not receive a genetic diagnosis by whole exome sequencing indicative of underlying regulatory variants. In contrast, whole genome sequencing allows the discovery of all genetic variants, but their significant number, coupled with a poor understanding of the non-coding genome, makes their prioritization challenging. Here, we demonstrate the power of directly sequencing transcriptomes by providing a genetic diagnosis for 11% (5 of 47) of unsolved mitochondrial disease patients and strong candidates for other patients. We found a median of 1 aberrantly expressed gene, 5 aberrant splicing events, and 6 mono-allelically expressed rare variants in patient-derived fibroblasts and established disease-causing roles for each kind. Private exons often arose from sites that are weakly spliced in other individuals, providing an important clue for future variant prioritization. One such intronic exon-creating variant was found in three unrelated families in the complex I assembly factor TIMMDC1, which we consequently established as a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants of Mendelian disorders and provides examples of intronic loss-of-function variants with pathological relevance.

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Posted July 29, 2016.
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Genetic diagnosis of Mendelian disorders via RNA sequencing
Laura S Kremer, Daniel M Bader, Christian Mertes, Robert Kopajtich, Garwin Pichler, Arcangela Iuso, Tobias B Haack, Elisabeth Graf, Thomas Schwarzmayr, Caterina Terrile, Eliška Koňaříková, Birgit Repp, Gabi Kastenmüller, Jerzy Adamski, Peter Lichtner, Christoph Leonhardt, Benoit Funalot, Alice Donati, Valeria Tiranti, Anne Lombes, Claude Jardel, Dieter Gläser, Robert W. Taylor, Daniele Ghezzi, Johannes A Mayr, Agnes Rötig, Peter Freisinger, Felix Distelmaier, Tim M Strom, Thomas Meitinger, Julien Gagneur, Holger Prokisch
bioRxiv 066738; doi: https://doi.org/10.1101/066738
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Genetic diagnosis of Mendelian disorders via RNA sequencing
Laura S Kremer, Daniel M Bader, Christian Mertes, Robert Kopajtich, Garwin Pichler, Arcangela Iuso, Tobias B Haack, Elisabeth Graf, Thomas Schwarzmayr, Caterina Terrile, Eliška Koňaříková, Birgit Repp, Gabi Kastenmüller, Jerzy Adamski, Peter Lichtner, Christoph Leonhardt, Benoit Funalot, Alice Donati, Valeria Tiranti, Anne Lombes, Claude Jardel, Dieter Gläser, Robert W. Taylor, Daniele Ghezzi, Johannes A Mayr, Agnes Rötig, Peter Freisinger, Felix Distelmaier, Tim M Strom, Thomas Meitinger, Julien Gagneur, Holger Prokisch
bioRxiv 066738; doi: https://doi.org/10.1101/066738

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