Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics.
Shamseldin, Hanan E
Alsaif, Hessa S
Al Ali, Hatoon
Alkuraya, Fowzan S.
KAUST DepartmentComputational Bioscience Research Center (CBRC)
Computer Science Program
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Structural and Functional Bioinformatics Group
Online Publication Date2020-06-17
Print Publication Date2020-12
Permanent link to this recordhttp://hdl.handle.net/10754/663747
MetadataShow full item record
AbstractBACKGROUND: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.
CitationMaddirevula, 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
SponsorsWe thank the study participants for their participation. We thank the Sequencing and Genotyping Core Facilities at KFSRHC and the Bioscience Core Lab at KAUST for their technical help.
RelationsIs Supplemented By:
Sateesh 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. DOI: 10.6084/m9.figshare.c.5026505.v1 Handle: 10754/664967
Except where otherwise noted, this item's license is described as This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders.
- Authors: Ewans LJ, Schofield D, Shrestha R, Zhu Y, Gayevskiy V, Ying K, Walsh C, Lee E, Kirk EP, Colley A, Ellaway C, Turner A, Mowat D, Worgan L, Freckmann ML, Lipke M, Sachdev R, Miller D, Field M, Dinger ME, Buckley MF, Cowley MJ, Roscioli T
- Issue date: 2018 Dec
- Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease.
- Authors: Gonorazky HD, Naumenko S, Ramani AK, Nelakuditi V, Mashouri P, Wang P, Kao D, Ohri K, Viththiyapaskaran S, Tarnopolsky MA, Mathews KD, Moore SA, Osorio AN, Villanova D, Kemaladewi DU, Cohn RD, Brudno M, Dowling JJ
- Issue date: 2019 Mar 7
- Inconsistency and features of single nucleotide variants detected in whole exome sequencing versus transcriptome sequencing: A case study in lung cancer.
- Authors: O'Brien TD, Jia P, Xia J, Saxena U, Jin H, Vuong H, Kim P, Wang Q, Aryee MJ, Mino-Kenudson M, Engelman JA, Le LP, Iafrate AJ, Heist RS, Pao W, Zhao Z
- Issue date: 2015 Jul 15
- Whole-Transcriptome Analysis by RNA Sequencing for Genetic Diagnosis of Mendelian Skin Disorders in the Context of Consanguinity.
- Authors: Youssefian L, Saeidian AH, Palizban F, Bagherieh A, Abdollahimajd F, Sotoudeh S, Mozafari N, Farahani RA, Mahmoudi H, Babashah S, Zabihi M, Zeinali S, Fortina P, Salas-Alanis JC, South AP, Vahidnezhad H, Uitto J
- Issue date: 2021 Jun 1
- Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing.
- Authors: Murdock DR, Dai H, Burrage LC, Rosenfeld JA, Ketkar S, Müller MF, Yépez VA, Gagneur J, Liu P, Chen S, Jain M, Zapata G, Bacino CA, Chao HT, Moretti P, Craigen WJ, Hanchard NA, Undiagnosed Diseases Network., Lee B
- Issue date: 2021 Jan 4