PT - JOURNAL ARTICLE AU - Laura S Kremer AU - Daniel M Bader AU - Christian Mertes AU - Robert Kopajtich AU - Garwin Pichler AU - Arcangela Iuso AU - Tobias B Haack AU - Elisabeth Graf AU - Thomas Schwarzmayr AU - Caterina Terrile AU - Eliška Koňařiková AU - Birgit Repp AU - Gabi Kastenmüller AU - Jerzy Adamski AU - Peter Lichtner AU - Christoph Leonhardt AU - Benoit Funalot AU - Alice Donati AU - Valeria Tiranti AU - Anne Lombes AU - Claude Jardel AU - Dieter Gläser AU - Robert W. Taylor AU - Daniele Ghezzi AU - Johannes A Mayr AU - Agnes Rötig AU - Peter Freisinger AU - Felix Distelmaier AU - Tim M Strom AU - Thomas Meitinger AU - Julien Gagneur AU - Holger Prokisch TI - Genetic diagnosis of Mendelian disorders via RNA sequencing AID - 10.1101/066738 DP - 2017 Jan 01 TA - bioRxiv PG - 066738 4099 - http://biorxiv.org/content/early/2017/01/16/066738.short 4100 - http://biorxiv.org/content/early/2017/01/16/066738.full AB - 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.