ArticleGenome medicine2024
Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach.
Article in Genome medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- RNA sequencing significantly improves HYDIN diagnosis and defines the effects of common deletions in primary ciliary dyskinesia.European journal of human genetics : EJHG · 2026Article
- Optimized RNA-seq workflow for routine diagnosis of mitochondrial diseases using aberrant expression analysis and phenotype-driven prioritization.European journal of human genetics : EJHG · 2026Article
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.Nature communications · 2026Article
- Transcription-based identification of uncharacterized genes in the human immune response.European journal of human genetics : EJHG · 2026Article
- HiFi long-read RNA sequencing enhances clinical diagnostics in rare disorders.European journal of human genetics : EJHG · 2026Article
- Translating transcriptomics analysis into diagnostic workflows: clinical variant identification and interpretation in hypothesis-driven and hypothesis-free approaches.EBioMedicine · 2026Article
- RNA Sequencing Resolves Cryptic Pathogenic Variants in Mitochondrial Disease.Annals of clinical and translational neurology · 2026Article
- Blood-based RNA-Seq of 5412 individuals with rare disease identifies new candidate diagnoses in the National Genomic Research Library.medRxiv : the preprint server for health 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
- Benchmarking RNA-seq Tools for Real-World Diagnostic Applications.medRxiv : the preprint server for health sciences · 2026Article
- A multidisciplinary RNA-guided approach to complement genomic analysis of unsolved patients with an inborn error of immunity.Frontiers in immunology · 2026Article
- RNA-Seq of Cultured Peripheral Blood Lymphocytes Improves Identification of Cryptic Splicing Defects in Rare Disease Diagnostics.Human mutation · 2026Article
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.bioRxiv : the preprint server for biology · 2025Article
- RNA sequencing provides functional insights and diagnostic resolution in previously unsolved rare disease cases.BMC medical genomics · 2025Article
- The utility of ultra-deep RNA sequencing in Mendelian disorder diagnostics.American journal of human genetics · 2025Article
- Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort.Genome medicine · 2025Article
- Translating Muscle RNAseq Into the Clinic for the Diagnosis of Muscle Diseases.Annals of clinical and translational neurology · 2025Article
- Assessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing.NPJ genomic medicine · 2025Article
- Cracking rare disorders: a new minimally invasive RNA-seq protocol.NPJ genomic medicine · 2025Article
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9 authors.
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Abstract
backgroundRNA sequencing (RNA-seq) is increasingly being used as a complementary tool to DNA sequencing in diagnostics where DNA analysis has been uninformative. RNA-seq enables the identification of aberrant splicing and aberrant gene expression, improving the interpretation of variants of unknown significance (VUSs), and provides the opportunity to scan the transcriptome for aberrant splicing and expression in relevant genes that may be the cause of a patient's phenotype. This work aims to investigate the feasibility of generating new diagnostic candidates in patients without a previously reported VUS using an RNA-seq-centric approach.
methodsWe systematically assessed the transcriptomic profiles of 86 patients with suspected Mendelian disorders, 38 of whom had no candidate sequence variant, using RNA from blood samples. Each VUS was visually inspected to search for splicing abnormalities. Once aberrant splicing was identified in cases with VUS, multiple open-source alternative splicing tools were used to investigate if they would identify what was observed in IGV. Expression outliers were detected using OUTRIDER. Diagnoses in cases without a VUS were explored using two separate strategies.
resultsRNA-seq allowed us to assess 71% of VUSs, detecting aberrant splicing in 14/48 patients with a VUS. We identified four new diagnoses by detecting novel aberrant splicing events in patients with no candidate sequence variants from prior DNA testing (n = 32) or where the candidate VUS did not affect splicing (n = 23). An additional diagnosis was made through the detection of skewed X-inactivation.
conclusionThis work demonstrates the utility of an RNA-centric approach in identifying novel diagnoses in patients without candidate VUSs. It underscores the utility of blood-based RNA analysis in improving diagnostic yields and highlights optimal approaches for such analyses.
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