Genetic diagnosis of Mendelian disorders via RNA sequencing

Nat Commun. 2017 Jun 12;8:15824. doi: 10.1038/ncomms15824.

Laura S Kremer ¹ ², Daniel M Bader ³ ⁴, Christian Mertes ³, Robert Kopajtich ¹ ², Garwin Pichler ⁵, Arcangela Iuso ¹ ², Tobias B Haack ¹ ², Elisabeth Graf ¹ ², Thomas Schwarzmayr ¹ ², Caterina Terrile ¹, Eliška Koňaříková ¹ ², Birgit Repp ¹ ², Gabi Kastenmüller ⁶, Jerzy Adamski ⁷, Peter Lichtner ¹, Christoph Leonhardt ⁸, Benoit Funalot ⁹, Alice Donati ¹⁰, Valeria Tiranti ¹¹, Anne Lombes ¹² ¹³ ¹⁴, Claude Jardel ¹² ¹⁵, Dieter Gläser ¹⁶, Robert W Taylor ¹⁷, Daniele Ghezzi ¹¹, Johannes A Mayr ¹⁸, Agnes Rötig ⁹, Peter Freisinger ¹⁹, Felix Distelmaier ²⁰, Tim M Strom ¹ ², Thomas Meitinger ¹ ², Julien Gagneur ³ ⁴, Holger Prokisch ¹ ²

Affiliations

1 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
2 Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
3 Department of Informatics, Technische Universität München, 85748 Garching, Germany.
4 Quantitative Biosciences Munich, Gene Center, Department of Biochemistry, Ludwig Maximilian Universität München, 81377 München, Germany.
5 Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany.
6 Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
7 Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
8 Neuropädiatrie, Neonatologie, 78050 Villingen-Schwenningen, Germany.
9 INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
10 Metabolic Unit, A. Meyer Children's Hospital, 50139 Florence, Italy.
11 Unit of Molecular Neurogenetics, Foundation IRCCS (Istituto di Ricovero e Cura a Carettere Scientifico) Neurological Institute 'Carlo Besta', 20126 Milan, Italy.
12 Inserm UMR 1016, Institut Cochin, 75014 Paris, France.
13 CNRS UMR 8104, Institut Cochin, 75014 Paris, France.
14 Université Paris V René Descartes, Institut Cochin, 75014 Paris, France.
15 AP/HP, GHU Pitié-Salpêtrière, Service de Biochimie Métabolique, 75013 Paris, France.
16 Genetikum, Genetic Counseling and Diagnostics, 89231 Neu-Ulm, Germany.
17 Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
18 Department of Pediatrics, Paracelsus Medical University, A-5020 Salzburg, Austria.
19 Department of Pediatrics, Klinikum Reutlingen, 72764 Reutlingen, Germany.
20 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.

PMID: 28604674 DOI: 10.1038/ncomms15824

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.

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