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 () and Holger Prokisch ()
Additional contact information
Laura S. Kremer: Institute of Human Genetics, Helmholtz Zentrum München
Daniel M. Bader: Technische Universität München
Christian Mertes: Technische Universität München
Robert Kopajtich: Institute of Human Genetics, Helmholtz Zentrum München
Garwin Pichler: Max-Planck Institute of Biochemistry
Arcangela Iuso: Institute of Human Genetics, Helmholtz Zentrum München
Tobias B. Haack: Institute of Human Genetics, Helmholtz Zentrum München
Elisabeth Graf: Institute of Human Genetics, Helmholtz Zentrum München
Thomas Schwarzmayr: Institute of Human Genetics, Helmholtz Zentrum München
Caterina Terrile: Institute of Human Genetics, Helmholtz Zentrum München
Eliška Koňaříková: Institute of Human Genetics, Helmholtz Zentrum München
Birgit Repp: Institute of Human Genetics, Helmholtz Zentrum München
Gabi Kastenmüller: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München
Jerzy Adamski: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health
Peter Lichtner: Institute of Human Genetics, Helmholtz Zentrum München
Christoph Leonhardt: Neuropädiatrie, Neonatologie
Benoit Funalot: INSERM U1163, Université Paris Descartes—Sorbonne Paris Cité, Institut Imagine
Alice Donati: Metabolic Unit, A. Meyer Children’s Hospital
Valeria Tiranti: Unit of Molecular Neurogenetics, Foundation IRCCS (Istituto di Ricovero e Cura a Carettere Scientifico) Neurological Institute ‘Carlo Besta’
Anne Lombes: Inserm UMR 1016, Institut Cochin
Claude Jardel: Inserm UMR 1016, Institut Cochin
Dieter Gläser: Genetikum, Genetic Counseling and Diagnostics
Robert W. Taylor: Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University
Daniele Ghezzi: Unit of Molecular Neurogenetics, Foundation IRCCS (Istituto di Ricovero e Cura a Carettere Scientifico) Neurological Institute ‘Carlo Besta’
Johannes A. Mayr: Paracelsus Medical University
Agnes Rötig: INSERM U1163, Université Paris Descartes—Sorbonne Paris Cité, Institut Imagine
Peter Freisinger: Klinikum Reutlingen
Felix Distelmaier: Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich-Heine-University Düsseldorf
Tim M. Strom: Institute of Human Genetics, Helmholtz Zentrum München
Thomas Meitinger: Institute of Human Genetics, Helmholtz Zentrum München
Julien Gagneur: Technische Universität München
Holger Prokisch: Institute of Human Genetics, Helmholtz Zentrum München

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Across a variety of Mendelian disorders, ∼50–75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private exons often arise from cryptic splice sites providing an important clue for variant prioritization. One such event is found in the complex I assembly factor TIMMDC1 establishing a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants and provides examples of intronic loss-of-function variants with pathological relevance.

Date: 2017
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DOI: 10.1038/ncomms15824

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