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Maddirevula, Sateesh; Kuwahara, 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.
Genome Biology, 06/2020, Volume: 21, Issue: 1Journal Article
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.
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