Trial reportThe Journal of clinical investigation2021
Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing.
Trial report in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 107 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Combining Exome and Transcriptome Data to Unravel the Genetic Basis of the Lissencephalies
Who cites it
107 citing papers in PubMed, 178 citations in OpenAlex.
- Arriving at a diagnosis: Effective strategies used by the Undiagnosed Diseases Network.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Beyond in silico prediction: multi-omics to identify a pathogenic deep intronic HNRNPK variant in Au-Kline syndrome.Journal of human genetics · 2026Article
- Long-read transcriptome analysis using IsoRanker for identifying pathogenic variants in Mendelian conditions.American journal of human genetics · 2026Article
- Technical Considerations for Blood RNA Sequencing in Genetic Testing: Evaluation of Globin Depletion Methods, Batch Effects, and Sample Types.Annals of laboratory medicine · 2026Article
- Article
- Technological Advances in Molecular Diagnostic Methods for Hereditary Diseases in Preconception and Prenatal Settings.Current issues in molecular biology · 2026Review
- Uncultured Amniocytes Enable Rapid and Clinically Informative Prenatal RNA Sequencing for Genetic Diagnosis.International journal of molecular sciences · 2026Article
- Genome sequencing for the diagnosis of rare disorders: The Brazilian Rare Genomes Project.HGG advances · 2026Article
- Evaluating the Utility of RNAseq in Prenatal Diagnostics: Expression Profiles of Cultured Chorionic Villus and Amniotic Fluid Samples.Prenatal diagnosis · 2026Article
- Fibroblast Transcriptomics in Molecular Diagnostics of a Comprehensive Dystonia Cohort.Annals of neurology · 2026Article
- Translating transcriptomics analysis into diagnostic workflows: clinical variant identification and interpretation in hypothesis-driven and hypothesis-free approaches.EBioMedicine · 2026Article
- HiFi long-read RNA sequencing enhances clinical diagnostics in rare disorders.European journal of human genetics : EJHG · 2026Article
- AXOLOTL: an accurate method for detecting aberrant gene expression in rare diseases using coexpression constraints.Bioinformatics (Oxford, England) · 2026Article
- RNA Sequencing Resolves Cryptic Pathogenic Variants in Mitochondrial Disease.Annals of clinical and translational neurology · 2026Article
- Targeted long-read RNA sequencing for rare disease diagnosis and variant interpretation.Science advances · 2026Article
- ASAH2 deficiency affects sphingolipid homeostasis and neuromotor control, causing a progressive neurological disorder.HGG advances · 2026Article
- Genetic analysis of neurodegenerative diseases.The Journal of clinical investigation · 2026Review
- Characterisation of Urine-Derived Cells for the Molecular Diagnosis of Rare Disorders.International journal of molecular sciences · 2026Article
- Accelerating rare disease diagnostics by linking DNA and RNA through an explainable and interactive RNA-guided workflow.NAR genomics and bioinformatics · 2026Article
- Benchmarking RNA-seq Tools for Real-World Diagnostic Applications.Research square · 2026Article
47 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 3 institutions in 2 countries.
Funding
Abstract
BACKGROUNDTranscriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq-guided method to diagnose individuals across a wide range of ages and clinical phenotypes.METHODSOne hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and skin fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network clinical site from 2014 to 2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis.RESULTSThe transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Skin fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts.CONCLUSIONSFor our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA.TRIAL REGISTRATIONNot applicable.FUNDINGNIH Common Fund, BCM Intellectual and Developmental Disabilities Research Center, Eunice Kennedy Shriver National Institute of Child Health & Human Development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.