Trial reportGenome biology2020
Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics.
Trial report in Genome biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 97 citations in OpenAlex.
- Technical Considerations for Blood RNA Sequencing in Genetic Testing: Evaluation of Globin Depletion Methods, Batch Effects, and Sample Types.Annals of laboratory medicine · 2026Article
- Congenital diarrhea/enteropathy due to a novel biallelic PERCC1 variant - a case-based review and variant analysis.Journal of human genetics · 2026Review
- Uncultured Amniocytes Enable Rapid and Clinically Informative Prenatal RNA Sequencing for Genetic Diagnosis.International journal of molecular sciences · 2026Article
- Building genomic medicine in Saudi Arabia.Nature genetics · 2026Article
- Molecular Genetics of 1α-Hydroxylase Deficiency in the Saudi Population.Journal of the Endocrine Society · 2026Article
- Clinical and Molecular Delineation ofHuman mutation · 2026Article
- Novel biallelic COL25A1 variants broaden the clinical spectrum from congenital cranial dysinnervation disorders to fetal lethal phenotypes.European journal of human genetics : EJHG · 2025Article
- Adult genomic medicine: lessons from a multisite study of 2700 patients.Genome medicine · 2025Article
- Cracking rare disorders: a new minimally invasive RNA-seq protocol.NPJ genomic medicine · 2025Article
- PERCC1 -Related Congenital Enteropathy.Clinical genetics · 2025Article
- Interpreting Variants of Uncertain Significance in PCD: Abnormal Splicing Caused by a Missense Variant of DNAAF3.Molecular genetics & genomic medicine · 2025Article
- Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach.Genome medicine · 2024Article
- RNA variant assessment using transactivation and transdifferentiation.American journal of human genetics · 2024Article
- Impact of genome build on RNA-seq interpretation and diagnostics.American journal of human genetics · 2024Article
- The clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing.American journal of human genetics · 2024Article
- Impact of genome build on RNA-seq interpretation and diagnostics.medRxiv : the preprint server for health sciences · 2024Article
- Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.Genome medicine · 2023Article
- Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families.Nature communications · 2023Article
- Novel SCN9A variant associated with congenital insensitivity to pain.Molecular biology reports · 2023Article
- Integrated multi-omics for rapid rare disease diagnosis on a national scale.Nature medicine · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
28 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAt 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.
resultsHere, 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.
conclusionsOur results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.
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