Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders
For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has n...
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| Published in: | American journal of human genetics Vol. 110; no. 2; p. 251 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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02.02.2023
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| ISSN: | 1537-6605, 1537-6605 |
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| Abstract | For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers. Analysis was performed by a user-friendly web application, and candidate pathogenic transcriptional events were confirmed by secondary assays. We identified intragenic deletions, monoallelic expression, and pseudoexonic insertions but also synonymous and non-synonymous variants with deleterious effects on transcription, increasing the diagnostic yield for NDDs by 13%. We found that cycloheximide treatment and exonic/intronic Z score analysis increased detection and resolution of aberrant splicing. Importantly, in one individual mis-splicing was found in a candidate gene nearly matching the individual's specific phenotype. However, pathogenic splicing occurred in another neuronal-expressed gene and provided a molecular diagnosis, stressing the need to customize RNA-seq. Lastly, our web browser application allowed custom analysis settings that facilitate diagnostic application and ranked pathogenic transcripts as top candidates. Our results demonstrate that RNA-seq is a complementary method in the genomic diagnosis of NDDs and, by providing accessible analysis with improved sensitivity, our transcriptome analysis approach facilitates wider implementation of RNA-seq in routine genome diagnostics. |
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| AbstractList | For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers. Analysis was performed by a user-friendly web application, and candidate pathogenic transcriptional events were confirmed by secondary assays. We identified intragenic deletions, monoallelic expression, and pseudoexonic insertions but also synonymous and non-synonymous variants with deleterious effects on transcription, increasing the diagnostic yield for NDDs by 13%. We found that cycloheximide treatment and exonic/intronic Z score analysis increased detection and resolution of aberrant splicing. Importantly, in one individual mis-splicing was found in a candidate gene nearly matching the individual's specific phenotype. However, pathogenic splicing occurred in another neuronal-expressed gene and provided a molecular diagnosis, stressing the need to customize RNA-seq. Lastly, our web browser application allowed custom analysis settings that facilitate diagnostic application and ranked pathogenic transcripts as top candidates. Our results demonstrate that RNA-seq is a complementary method in the genomic diagnosis of NDDs and, by providing accessible analysis with improved sensitivity, our transcriptome analysis approach facilitates wider implementation of RNA-seq in routine genome diagnostics. For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers. Analysis was performed by a user-friendly web application, and candidate pathogenic transcriptional events were confirmed by secondary assays. We identified intragenic deletions, monoallelic expression, and pseudoexonic insertions but also synonymous and non-synonymous variants with deleterious effects on transcription, increasing the diagnostic yield for NDDs by 13%. We found that cycloheximide treatment and exonic/intronic Z score analysis increased detection and resolution of aberrant splicing. Importantly, in one individual mis-splicing was found in a candidate gene nearly matching the individual's specific phenotype. However, pathogenic splicing occurred in another neuronal-expressed gene and provided a molecular diagnosis, stressing the need to customize RNA-seq. Lastly, our web browser application allowed custom analysis settings that facilitate diagnostic application and ranked pathogenic transcripts as top candidates. Our results demonstrate that RNA-seq is a complementary method in the genomic diagnosis of NDDs and, by providing accessible analysis with improved sensitivity, our transcriptome analysis approach facilitates wider implementation of RNA-seq in routine genome diagnostics.For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers. Analysis was performed by a user-friendly web application, and candidate pathogenic transcriptional events were confirmed by secondary assays. We identified intragenic deletions, monoallelic expression, and pseudoexonic insertions but also synonymous and non-synonymous variants with deleterious effects on transcription, increasing the diagnostic yield for NDDs by 13%. We found that cycloheximide treatment and exonic/intronic Z score analysis increased detection and resolution of aberrant splicing. Importantly, in one individual mis-splicing was found in a candidate gene nearly matching the individual's specific phenotype. However, pathogenic splicing occurred in another neuronal-expressed gene and provided a molecular diagnosis, stressing the need to customize RNA-seq. Lastly, our web browser application allowed custom analysis settings that facilitate diagnostic application and ranked pathogenic transcripts as top candidates. Our results demonstrate that RNA-seq is a complementary method in the genomic diagnosis of NDDs and, by providing accessible analysis with improved sensitivity, our transcriptome analysis approach facilitates wider implementation of RNA-seq in routine genome diagnostics. |
| Author | Mancini, Grazia M S Dekker, Jordy Smits, Daphne J Joosten, Marieke Kievit, Anneke J A de Valk, Walter G Sadeghi Niaraki, Farah Hoefsloot, Lies H Wilke, Martina Geeven, Geert van Ierland, Yvette van Unen, Leontine M A Verheijen, Frans W Saris, Jasper J Verhoeven, Virginie J M Huidekoper, Hidde H van Veghel-Plandsoen, Monique M van Ham, Tjakko J Elfferich, Peter van de Laar, Ingrid M B H Williams, Monique Douben, Hannie Schot, Rachel Bongaerts, Michiel Nellist, Mark Kasteleijn, Esmee van der Sterre, Marianne L T Hoogeveen-Westerveld, Marianne Monfils, Kathryn |
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organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 6 givenname: Kathryn surname: Monfils fullname: Monfils, Kathryn organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 7 givenname: Hannie surname: Douben fullname: Douben, Hannie organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 8 givenname: Peter surname: Elfferich fullname: Elfferich, Peter organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 9 givenname: Esmee surname: Kasteleijn fullname: Kasteleijn, Esmee organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 10 givenname: Leontine M A surname: van Unen fullname: van Unen, Leontine M A organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 11 givenname: Geert surname: Geeven fullname: Geeven, Geert organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 12 givenname: Jasper J surname: Saris fullname: Saris, Jasper J organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 13 givenname: Yvette surname: van Ierland fullname: van Ierland, Yvette organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 14 givenname: Frans W surname: Verheijen fullname: Verheijen, Frans W organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 15 givenname: Marianne L T surname: van der Sterre fullname: van der Sterre, Marianne L T organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 16 givenname: Farah surname: Sadeghi Niaraki fullname: Sadeghi Niaraki, Farah organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 17 givenname: Daphne J surname: Smits fullname: Smits, Daphne J organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 18 givenname: Hidde H surname: Huidekoper fullname: Huidekoper, Hidde H organization: Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 19 givenname: Monique surname: Williams fullname: Williams, Monique organization: Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 20 givenname: Martina surname: Wilke fullname: Wilke, Martina organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 21 givenname: Virginie J M surname: Verhoeven fullname: Verhoeven, Virginie J M organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 22 givenname: Marieke surname: Joosten fullname: Joosten, Marieke organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 23 givenname: Anneke J A surname: Kievit fullname: Kievit, Anneke J A organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 24 givenname: Ingrid M B H surname: van de Laar fullname: van de Laar, Ingrid M B H organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 25 givenname: Lies H surname: Hoefsloot fullname: Hoefsloot, Lies H organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 26 givenname: Marianne surname: Hoogeveen-Westerveld fullname: Hoogeveen-Westerveld, Marianne organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 27 givenname: Mark surname: Nellist fullname: Nellist, Mark organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 28 givenname: Grazia M S surname: Mancini fullname: Mancini, Grazia M S organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands – sequence: 29 givenname: Tjakko J surname: van Ham fullname: van Ham, Tjakko J email: t.vanham@erasmusmc.nl organization: Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 Rotterdam, the Netherlands. Electronic address: t.vanham@erasmusmc.nl |
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| Keywords | RNA-sequencing transcriptomics molecular diagnostics mRNA splicing neurodevelopmental disorder web browser application |
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| SubjectTerms | Cycloheximide Gene Expression Profiling Humans Neurodevelopmental Disorders - diagnosis Neurodevelopmental Disorders - genetics RNA-Seq Sequence Analysis, RNA - methods |
| Title | Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders |
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