Genetic diagnosis of Mendelian disorders via RNA sequencing

Kremer LS, Bader DM, Mertes C, Kopajtich R, Pichler G, Iuso A, Haack TB, Graf E, Schwarzmayr T, Terrile C, Konarikova E, Repp B, Kastenmueller G, Adamski J, Lichtner P, Leonhardt C, Funalot B, Donati A, Tiranti V, Lombes A, Jardel C, Glaeser D, Taylor RW, Ghezzi D, Mayr JA, Roetig A, Freisinger P, Distelmaier F, Strom TM, Meitinger T, Gagneur J, Prokisch H (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 8

Article Number: 15824

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.

Involved external institutions

Kreiskliniken Reutlingen DE Germany (DE) Heinrich-Heine-Universität Düsseldorf DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry DE Germany (DE) University of Paris 5 - René Descartes / Université Paris V René Descartes FR France (FR) Azienda Ospedaliera Universitaria Meyer IT Italy (IT) Fondazione IRCCS: Istituto Nazionale dei Tumori IT Italy (IT) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) FR France (FR) genetikum – Genetische Beratung & Diagnostik DE Germany (DE) Newcastle University GB United Kingdom (GB) Paracelsus Medizinische Privatuniversität AT Austria (AT)

How to cite

APA:

Kremer, L.S., Bader, D.M., Mertes, C., Kopajtich, R., Pichler, G., Iuso, A.,... Prokisch, H. (2017). Genetic diagnosis of Mendelian disorders via RNA sequencing. Nature Communications, 8. https://doi.org/10.1038/ncomms15824

MLA:

Kremer, Laura S., et al. "Genetic diagnosis of Mendelian disorders via RNA sequencing." Nature Communications 8 (2017).

BibTeX: Download