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000163695 037__ $$aDZNE-2022-00439
000163695 041__ $$aEnglish
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000163695 1001_ $$aYépez, Vicente A$$b0
000163695 245__ $$aClinical implementation of RNA sequencing for Mendelian disease diagnostics.
000163695 260__ $$aLondon$$bBioMed Central$$c2022
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000163695 520__ $$aLack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics.We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage.We detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions.Together, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics.
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000163695 650_7 $$2Other$$aGenetic diagnostics
000163695 650_7 $$2Other$$aMendelian diseases
000163695 650_7 $$2Other$$aRNA-seq
000163695 650_7 $$063231-63-0$$2NLM Chemicals$$aRNA
000163695 650_2 $$2MeSH$$aExome Sequencing
000163695 650_2 $$2MeSH$$aAlleles
000163695 650_2 $$2MeSH$$aHumans
000163695 650_2 $$2MeSH$$aRNA
000163695 650_2 $$2MeSH$$aSequence Analysis, RNA: methods
000163695 650_2 $$2MeSH$$aTranscriptome
000163695 650_2 $$2MeSH$$aWhole Exome Sequencing
000163695 7001_ $$aGusic, Mirjana$$b1
000163695 7001_ $$aKopajtich, Robert$$b2
000163695 7001_ $$aMertes, Christian$$b3
000163695 7001_ $$aSmith, Nicholas H$$b4
000163695 7001_ $$aAlston, Charlotte L$$b5
000163695 7001_ $$aBan, Rui$$b6
000163695 7001_ $$aBeblo, Skadi$$b7
000163695 7001_ $$aBerutti, Riccardo$$b8
000163695 7001_ $$aBlessing, Holger$$b9
000163695 7001_ $$aCiara, Elżbieta$$b10
000163695 7001_ $$aDistelmaier, Felix$$b11
000163695 7001_ $$aFreisinger, Peter$$b12
000163695 7001_ $$aHäberle, Johannes$$b13
000163695 7001_ $$aHayflick, Susan J$$b14
000163695 7001_ $$aHempel, Maja$$b15
000163695 7001_ $$aItkis, Yulia S$$b16
000163695 7001_ $$aKishita, Yoshihito$$b17
000163695 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b18$$udzne
000163695 7001_ $$aKrylova, Tatiana D$$b19
000163695 7001_ $$aLamperti, Costanza$$b20
000163695 7001_ $$aLenz, Dominic$$b21
000163695 7001_ $$aMakowski, Christine$$b22
000163695 7001_ $$aMosegaard, Signe$$b23
000163695 7001_ $$0P:(DE-2719)2810465$$aMüller, Michaela$$b24$$udzne
000163695 7001_ $$aMuñoz-Pujol, Gerard$$b25
000163695 7001_ $$aNadel, Agnieszka$$b26
000163695 7001_ $$aOhtake, Akira$$b27
000163695 7001_ $$aOkazaki, Yasushi$$b28
000163695 7001_ $$aProcopio, Elena$$b29
000163695 7001_ $$aSchwarzmayr, Thomas$$b30
000163695 7001_ $$aSmet, Joél$$b31
000163695 7001_ $$aStaufner, Christian$$b32
000163695 7001_ $$aStenton, Sarah L$$b33
000163695 7001_ $$aStrom, Tim M$$b34
000163695 7001_ $$aTerrile, Caterina$$b35
000163695 7001_ $$aTort, Frederic$$b36
000163695 7001_ $$aVan Coster, Rudy$$b37
000163695 7001_ $$aVanlander, Arnaud$$b38
000163695 7001_ $$aWagner, Matias$$b39
000163695 7001_ $$aXu, Manting$$b40
000163695 7001_ $$aFang, Fang$$b41
000163695 7001_ $$aGhezzi, Daniele$$b42
000163695 7001_ $$aMayr, Johannes A$$b43
000163695 7001_ $$aPiekutowska-Abramczuk, Dorota$$b44
000163695 7001_ $$aRibes, Antonia$$b45
000163695 7001_ $$aRötig, Agnès$$b46
000163695 7001_ $$aTaylor, Robert W$$b47
000163695 7001_ $$aWortmann, Saskia B$$b48
000163695 7001_ $$aMurayama, Kei$$b49
000163695 7001_ $$0P:(DE-2719)9000207$$aMeitinger, Thomas$$b50$$udzne
000163695 7001_ $$aGagneur, Julien$$b51
000163695 7001_ $$aProkisch, Holger$$b52
000163695 773__ $$0PERI:(DE-600)2484394-5$$a10.1186/s13073-022-01019-9$$gVol. 14, no. 1, p. 38$$n1$$p38$$tGenome medicine$$v14$$x1756-994X$$y2022
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