Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics.
Type
ArticleAuthors
Maddirevula, SateeshKuwahara, Hiroyuki
Ewida, Nour
Shamseldin, Hanan E
Patel, Nisha
AlZahrani, Fatema
AlSheddi, Tarfa
AlObeid, Eman
Alenazi, Mona
Alsaif, Hessa S
Alqahtani, Maha
AlAli, Maha
Al Ali, Hatoon
Helaby, Rana
Ibrahim, Niema
Abdulwahab, Firdous
Hashem, Mais
Hanna, Nadine
Monies, Dorota
Derar, Nada
Alsagheir, Afaf
Alhashem, Amal
Alsaleem, Badr
Alhebbi, Hamoud
Wali, Sami
Umarov, Ramzan
Gao, Xin

Alkuraya, Fowzan S.

KAUST Department
Computational Bioscience Research Center (CBRC)Computer Science Program
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Structural and Functional Bioinformatics Group
Date
2020-06-17Online Publication Date
2020-06-17Print Publication Date
2020-12Submitted Date
2019-10-10Permanent link to this record
http://hdl.handle.net/10754/663747
Metadata
Show full item recordAbstract
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.Citation
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/s13059-020-02053-9Sponsors
We 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.Publisher
Springer Science and Business Media LLCJournal
Genome biologyPubMed ID
32552793Relations
Is Supplemented By:- [Dataset]
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
ae974a485f413a2113503eed53cd6c53
10.1186/s13059-020-02053-9
Scopus Count
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