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 NatureJournal
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
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.
Related articles
- 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
- The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.
- Authors: Monies D, Abouelhoda M, AlSayed M, Alhassnan Z, Alotaibi M, Kayyali H, Al-Owain M, Shah A, Rahbeeni Z, Al-Muhaizea MA, Alzaidan HI, Cupler E, Bohlega S, Faqeih E, Faden M, Alyounes B, Jaroudi D, Goljan E, Elbardisy H, Akilan A, Albar R, Aldhalaan H, Gulab S, Chedrawi A, Al Saud BK, Kurdi W, Makhseed N, Alqasim T, El Khashab HY, Al-Mousa H, Alhashem A, Kanaan I, Algoufi T, Alsaleem K, Basha TA, Al-Murshedi F, Khan S, Al-Kindy A, Alnemer M, Al-Hajjar S, Alyamani S, Aldhekri H, Al-Mehaidib A, Arnaout R, Dabbagh O, Shagrani M, Broering D, Tulbah M, Alqassmi A, Almugbel M, AlQuaiz M, Alsaman A, Al-Thihli K, Sulaiman RA, Al-Dekhail W, Alsaegh A, Bashiri FA, Qari A, Alhomadi S, Alkuraya H, Alsebayel M, Hamad MH, Szonyi L, Abaalkhail F, Al-Mayouf SM, Almojalli H, Alqadi KS, Elsiesy H, Shuaib TM, Seidahmed MZ, Abosoudah I, Akleh H, AlGhonaium A, Alkharfy TM, Al Mutairi F, Eyaid W, Alshanbary A, Sheikh FR, Alsohaibani FI, Alsonbul A, Al Tala S, Balkhy S, Bassiouni R, Alenizi AS, Hussein MH, Hassan S, Khalil M, Tabarki B, Alshahwan S, Oshi A, Sabr Y, Alsaadoun S, Salih MA, Mohamed S, Sultana H, Tamim A, El-Haj M, Alshahrani S, Bubshait DK, Alfadhel M, Faquih T, El-Kalioby M, Subhani S, Shah Z, Moghrabi N, Meyer BF, Alkuraya FS
- Issue date: 2017 Aug
- Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.
- Authors: LaDuca H, Farwell KD, Vuong H, Lu HM, Mu W, Shahmirzadi L, Tang S, Chen J, Bhide S, Chao EC
- Issue date: 2017
- Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.
- Authors: Lee H, Huang AY, Wang LK, Yoon AJ, Renteria G, Eskin A, Signer RH, Dorrani N, Nieves-Rodriguez S, Wan J, Douine ED, Woods JD, Dell'Angelica EC, Fogel BL, Martin MG, Butte MJ, Parker NH, Wang RT, Shieh PB, Wong DA, Gallant N, Singh KE, Tavyev Asher YJ, Sinsheimer JS, Krakow D, Loo SK, Allard P, Papp JC, Undiagnosed Diseases Network, Palmer CGS, Martinez-Agosto JA, Nelson SF
- Issue date: 2020 Mar
- Clinical implementation of RNA sequencing for Mendelian disease diagnostics.
- Authors: Yépez VA, Gusic M, Kopajtich R, Mertes C, Smith NH, Alston CL, Ban R, Beblo S, Berutti R, Blessing H, Ciara E, Distelmaier F, Freisinger P, Häberle J, Hayflick SJ, Hempel M, Itkis YS, Kishita Y, Klopstock T, Krylova TD, Lamperti C, Lenz D, Makowski C, Mosegaard S, Müller MF, Muñoz-Pujol G, Nadel A, Ohtake A, Okazaki Y, Procopio E, Schwarzmayr T, Smet J, Staufner C, Stenton SL, Strom TM, Terrile C, Tort F, Van Coster R, Vanlander A, Wagner M, Xu M, Fang F, Ghezzi D, Mayr JA, Piekutowska-Abramczuk D, Ribes A, Rötig A, Taylor RW, Wortmann SB, Murayama K, Meitinger T, Gagneur J, Prokisch H
- Issue date: 2022 Apr 5