Clinical implementation of RNA sequencing for Mendelian disease diagnostics
Background Lack 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...
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
05 April 2022
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| In: |
Genome medicine
Year: 2022, Jahrgang: 14, Pages: 1-16 |
| ISSN: | 1756-994X |
| DOI: | 10.1186/s13073-022-01019-9 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1186/s13073-022-01019-9 Verlag, lizenzpflichtig, Volltext: https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-022-01019-9 
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| Verfasserangaben: | Vicente A. Yepez, Mirjana Gusic, Robert Kopajtich, Christian Mertes, Nicholas H. Smith, Charlotte L. Alston, Rui Ban, Skadi Beblo, Riccardo Berutti, Holger Blessing, Elzbieta Ciara, Felix Distelmaier, Peter Freisinger, Johannes Haeberle, Susan J. Hayflick, Maja Hempel, Yulia S. Itkis, Yoshihito Kishita, Thomas Klopstock, Tatiana D. Krylova, Costanza Lamperti, Dominic Lenz, Christine Makowski, Signe Mosegaard, Michaela F. Mueller, Gerard Munoz-Pujol, Agnieszka Nadel, Akira Ohtake, Yasushi Okazaki, Elena Procopio, Thomas Schwarzmayr, Joel Smet, Christian Staufner, Sarah L. Stenton, Tim M. Strom, Caterina Terrile, Frederic Tort, Rudy Van Coster, Arnaud Vanlander, Matias Wagner, Manting Xu, Fang Fang, Daniele Ghezzi, Johannes A. Mayr, Dorota Piekutowska-Abramczuk, Antonia Ribes, Agnes Roetig, Robert W. Taylor, Saskia B. Wortmann, Kei Murayama, Thomas Meitinger, Julien Gagneur and Holger Prokisch |
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| 100 | 1 | |a Yépez, Vicente |e VerfasserIn |0 (DE-588)1278919821 |0 (DE-627)1831826623 |4 aut | |
| 245 | 1 | 0 | |a Clinical implementation of RNA sequencing for Mendelian disease diagnostics |c Vicente A. Yepez, Mirjana Gusic, Robert Kopajtich, Christian Mertes, Nicholas H. Smith, Charlotte L. Alston, Rui Ban, Skadi Beblo, Riccardo Berutti, Holger Blessing, Elzbieta Ciara, Felix Distelmaier, Peter Freisinger, Johannes Haeberle, Susan J. Hayflick, Maja Hempel, Yulia S. Itkis, Yoshihito Kishita, Thomas Klopstock, Tatiana D. Krylova, Costanza Lamperti, Dominic Lenz, Christine Makowski, Signe Mosegaard, Michaela F. Mueller, Gerard Munoz-Pujol, Agnieszka Nadel, Akira Ohtake, Yasushi Okazaki, Elena Procopio, Thomas Schwarzmayr, Joel Smet, Christian Staufner, Sarah L. Stenton, Tim M. Strom, Caterina Terrile, Frederic Tort, Rudy Van Coster, Arnaud Vanlander, Matias Wagner, Manting Xu, Fang Fang, Daniele Ghezzi, Johannes A. Mayr, Dorota Piekutowska-Abramczuk, Antonia Ribes, Agnes Roetig, Robert W. Taylor, Saskia B. Wortmann, Kei Murayama, Thomas Meitinger, Julien Gagneur and Holger Prokisch |
| 264 | 1 | |c 05 April 2022 | |
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| 500 | |a Published 05 April 2022 | ||
| 500 | |a Gesehen am 23.01.2023 | ||
| 520 | |a Background Lack 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. Methods 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. Results 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. Conclusion Together, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics. | ||
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| 650 | 4 | |a defect | |
| 650 | 4 | |a deficiency | |
| 650 | 4 | |a gene-expression | |
| 650 | 4 | |a Genetic diagnostics | |
| 650 | 4 | |a genomics | |
| 650 | 4 | |a Mendelian diseases | |
| 650 | 4 | |a mitochondrial disease | |
| 650 | 4 | |a mutations cause | |
| 650 | 4 | |a onset | |
| 650 | 4 | |a RNA-seq | |
| 650 | 4 | |a variants | |
| 700 | 1 | |a Gusic, Mirjana |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kopajtich, Robert |e VerfasserIn |4 aut | |
| 700 | 1 | |a Mertes, Christian |e VerfasserIn |4 aut | |
| 700 | 1 | |a Smith, Nicholas H. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Alston, Charlotte L. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ban, Rui |e VerfasserIn |4 aut | |
| 700 | 1 | |a Beblo, Skadi |e VerfasserIn |4 aut | |
| 700 | 1 | |a Berutti, Riccardo |e VerfasserIn |4 aut | |
| 700 | 1 | |a Blessing, Holger |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ciara, Elzbieta |e VerfasserIn |4 aut | |
| 700 | 1 | |a Distelmaier, Felix |e VerfasserIn |4 aut | |
| 700 | 1 | |a Freisinger, Peter |e VerfasserIn |4 aut | |
| 700 | 1 | |a Haeberle, Johannes |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hayflick, Susan J. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Hempel, Maja |e VerfasserIn |4 aut | |
| 700 | 1 | |a Itkis, Yulia S. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kishita, Yoshihito |e VerfasserIn |4 aut | |
| 700 | 1 | |a Klopstock, Thomas |e VerfasserIn |4 aut | |
| 700 | 1 | |a Krylova, Tatiana D. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Lamperti, Costanza |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Mueller, Michaela F. |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Procopio, Elena |e VerfasserIn |4 aut | |
| 700 | 1 | |a Schwarzmayr, Thomas |e VerfasserIn |4 aut | |
| 700 | 1 | |a Smet, Joel |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Stenton, Sarah L. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Strom, Tim M. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Terrile, Caterina |e VerfasserIn |4 aut | |
| 700 | 1 | |a Tort, Frederic |e VerfasserIn |4 aut | |
| 700 | 1 | |a Van Coster, Rudy |e VerfasserIn |4 aut | |
| 700 | 1 | |a Vanlander, Arnaud |e VerfasserIn |4 aut | |
| 700 | 1 | |a Wagner, Matias |e VerfasserIn |4 aut | |
| 700 | 1 | |a Xu, Manting |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Ghezzi, Daniele |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Taylor, Robert W. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Wortmann, Saskia B. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Murayama, Kei |e VerfasserIn |4 aut | |
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