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Genetic diagnosis of Mendelian disorders via RNA sequencing

Lookup NU author(s): Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

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

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2017

Volume: 8

Online publication date: 12/06/2017

Acceptance date: 28/04/2017

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/ncomms15824

DOI: 10.1038/ncomms15824


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