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  Genetic diagnosis of Mendelian disorders via RNA sequencing

Kremer, L. S., Bader, D. M., Mertes, C., Kopajtich, R., Pichler, G., Iuso, A., et al. (2017). Genetic diagnosis of Mendelian disorders via RNA sequencing. Nature Communications, 8: 15824. doi:10.1038/ncomms15824.

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 Creators:
Kremer, Laura S.1, Author
Bader, Daniel M.1, Author
Mertes, Christian1, Author
Kopajtich, Robert1, Author
Pichler, Garwin2, Author              
Iuso, Arcangela1, Author
Haack, Tobias B.1, Author
Graf, Elisabeth1, Author
Schwarzmayr, Thomas1, Author
Terrile, Caterina1, Author
Konarikova, Eliska1, Author
Repp, Birgit1, Author
Kastenmueller, Gabi1, Author
Adamski, Jerzy1, Author
Lichtner, Peter1, Author
Leonhardt, Christoph1, Author
Funalot, Benoit1, Author
Donati, Alice1, Author
Tiranti, Valeria1, Author
Lombes, Anne1, Author
Jardel, Claude1, AuthorGlaeser, Dieter1, AuthorTaylor, Robert W.1, AuthorGhezzi, Daniele1, AuthorMayr, Johannes A.1, AuthorRoetig, Agnes1, AuthorFreisinger, Peter1, AuthorDistelmaier, Felix1, AuthorStrom, Tim M.1, AuthorMeitinger, Thomas1, AuthorGagneur, Julien1, AuthorProkisch, Holger1, Author more..
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: RANDOM MONOALLELIC EXPRESSION; PERRAULT SYNDROME; COMPLEX I; MUTATIONS; TOOL; DISEASE; SNP; MITOCHONDRIA; ASSOCIATION; DEFICIENCYScience & Technology - Other Topics;
 Abstract: Across a variety of Mendelian disorders, similar to 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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Language(s): eng - English
 Dates: 2017-06-12
 Publication Status: Published online
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000403069900001
DOI: 10.1038/ncomms15824
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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 8 Sequence Number: 15824 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723