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dc.contributor.authorMaddirevula, Sateesh
dc.contributor.authorKuwahara, Hiroyuki
dc.contributor.authorEwida, Nour
dc.contributor.authorShamseldin, Hanan E.
dc.contributor.authorPatel, Nisha
dc.contributor.authorAlZahrani, Fatema
dc.contributor.authorAlSheddi, Tarfa
dc.contributor.authorAlObeid, Eman
dc.contributor.authorAlenazi, Mona
dc.contributor.authorAlsaif, Hessa S.
dc.contributor.authorAlqahtani, Maha
dc.contributor.authorAlAli, Maha
dc.contributor.authorAl Ali, Hatoon
dc.contributor.authorHelaby, Rana
dc.contributor.authorIbrahim, Niema
dc.contributor.authorAbdulwahab, Firdous
dc.contributor.authorHashem, Mais
dc.contributor.authorHanna, Nadine
dc.contributor.authorMonies, Dorota
dc.contributor.authorDerar, Nada
dc.contributor.authorAlsagheir, Afaf
dc.contributor.authorAlhashem, Amal
dc.contributor.authorAlsaleem, Badr
dc.contributor.authorAlhebbi, Hamoud
dc.contributor.authorWali, Sami
dc.contributor.authorUmarov, Ramzan
dc.contributor.authorGao, Xin
dc.contributor.authorAlkuraya, Fowzan S.
dc.date.accessioned2020-09-07T07:55:48Z
dc.date.available2020-09-07T07:55:48Z
dc.date.issued2020
dc.identifier.citationSateesh Maddirevula, Kuwahara, H., Ewida, N., Shamseldin, H. E., Patel, N., Alzahrani, F., Tarfa AlSheddi, AlObeid, E., Alenazi, M., Hessa S. Alsaif, Alqahtani, M., AlAli, M., Hatoon Al Ali, Helaby, R., Niema Ibrahim, Firdous Abdulwahab, Hashem, M., Hanna, N., Monies, D., … Alkuraya, F. S. (2020). Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics. figshare. https://doi.org/10.6084/M9.FIGSHARE.C.5026505.V1
dc.identifier.doi10.6084/m9.figshare.c.5026505.v1
dc.identifier.urihttp://hdl.handle.net/10754/664968
dc.description.abstractAbstract Background At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which non-coding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce. Results Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all “solved” cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received “negative” clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders. Conclusions Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.
dc.publisherfigshare
dc.subjectGenetics
dc.subjectFOS: Biological sciences
dc.titleAnalysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics
dc.typeDataset
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.contributor.departmentComputer Science Program
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
dc.contributor.departmentStructural and Functional Bioinformatics Group
dc.contributor.institutionDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
dc.contributor.institutionDépartement de génétique, AP-HP, Hôpital Bichat, Université de Paris, LVTS INSERM U1148, Paris, France.
dc.contributor.institutionDepartment of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
dc.contributor.institutionDeparmtent of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
dc.contributor.institutionDepartment of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
dc.contributor.institutionDivision of Pediatric Gastroenterology, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
kaust.personKuwahara, Hiroyuki
kaust.personUmarov, Ramzan
kaust.personGao, Xin
dc.relation.issupplementtoDOI:10.1186/s13059-020-02053-9
display.relations<b> Is Supplement To:</b><br/> <ul> <li><i>[Article]</i> <br/> Maddirevula, S., Kuwahara, H., Ewida, N., Shamseldin, H. E., Patel, N., Alzahrani, F., … Alkuraya, F. S. (2020). Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics. Genome Biology, 21(1). doi:10.1186/s13059-020-02053-9. DOI: <a href="https://doi.org/10.1186/s13059-020-02053-9" >10.1186/s13059-020-02053-9</a> HANDLE: <a href="http://hdl.handle.net/10754/663747">10754/663747</a></li></ul>


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