@article {Kremer066738, author = {Laura S Kremer and Daniel M Bader and Christian Mertes and Robert Kopajtich and Garwin Pichler and Arcangela Iuso and Tobias B Haack and Elisabeth Graf and Thomas Schwarzmayr and Caterina Terrile and Eli{\v s}ka Ko{\v n}a{\v r}ikov{\'a} and Birgit Repp and Gabi Kastenm{\"u}ller and Jerzy Adamski and Peter Lichtner and Christoph Leonhardt and Benoit Funalot and Alice Donati and Valeria Tiranti and Anne Lombes and Claude Jardel and Dieter Gl{\"a}ser and Robert W. Taylor and Daniele Ghezzi and Johannes A Mayr and Agnes R{\"o}tig and Peter Freisinger and Felix Distelmaier and Tim M Strom and Thomas Meitinger and Julien Gagneur and Holger Prokisch}, title = {Genetic diagnosis of Mendelian disorders via RNA sequencing}, elocation-id = {066738}, year = {2017}, doi = {10.1101/066738}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Across a large variety of Mendelian disorders, ~50-75\% of patients do not receive a genetic diagnosis by whole exome sequencing indicative of underlying disease-causing variants in non-coding regions. In contrast, whole genome sequencing facilitates the discovery of all genetic variants, but their sizeable number, coupled with a poor understanding of the non-coding genome, makes their prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to provide a confirmed genetic diagnosis for 10\% (5 of 48) of undiagnosed mitochondrial disease patients and identify strong candidate genes for patients remaining without diagnosis. 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.}, URL = {https://www.biorxiv.org/content/early/2017/01/16/066738}, eprint = {https://www.biorxiv.org/content/early/2017/01/16/066738.full.pdf}, journal = {bioRxiv} }