Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics

  • Sateesh Maddirevula (Creator)
  • Hiroyuki Kuwahara (Creator)
  • Nour Ewida (Creator)
  • Hanan E. Shamseldin (Creator)
  • Nisha Patel (Creator)
  • Fatema AlZahrani (Creator)
  • Tarfa AlSheddi (Creator)
  • Eman Alobeid (Creator)
  • Mona Alenazi (Creator)
  • Hessa S. Alsaif (Creator)
  • Maha Alqahtani (Creator)
  • Maha AlAli (Creator)
  • Hatoon Al Ali (Creator)
  • Rana Helaby (Creator)
  • Niema Ibrahim (Creator)
  • Firdous Abdulwahab (Creator)
  • Mais Hashem (Creator)
  • Nadine Hanna (Creator)
  • Dorota Monies (Creator)
  • Nada Derar (Creator)
  • Afaf Alsagheir (Creator)
  • Amal Alhashem (Creator)
  • Badr Alsaleem (Creator)
  • Hamoud Alhebbi (Creator)
  • Sami Wali (Creator)
  • Ramzan Umarov (Creator)
  • Xin Gao (Creator)
  • Fowzan S. Alkuraya (Creator)



Abstract 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.
Date made available2020

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