ArticleGenome medicine2022
Clinical implementation of RNA sequencing for Mendelian disease diagnostics.
Article in Genome medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 138 papers.
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138 citing papers in PubMed, 193 citations in OpenAlex.
- Integrative and systematic genomic approaches to improve diagnosis in rare and undiagnosed diseases: results from the RareBoost project.European journal of human genetics : EJHG · 2026Article
- Long-read transcriptome analysis using IsoRanker for identifying pathogenic variants in Mendelian conditions.American journal of human genetics · 2026Article
- A novel synonymous TSC2 mutation in a Chinese family leads to tuberous sclerosis type 2 by disrupting Normal pre-mRNA splicing.Journal, genetic engineering & biotechnology · 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
- Technological Advances in Molecular Diagnostic Methods for Hereditary Diseases in Preconception and Prenatal Settings.Current issues in molecular biology · 2026Review
- Advances in Primary Mitochondrial Diseases: Diagnosis, Natural History Studies and Clinical Trials.Genes · 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
- Implementation of a medical genomics program for rare diseases in Uruguay.Orphanet journal of rare diseases · 2026Article
- Article
- 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
- The utility and advantages of exome and genome sequencing in pediatric kidney disease diagnosis.Childhood kidney diseases · 2026Review
- Nanopore direct RNA sequencing and the epitranscriptome: Advances in mapping native RNA landscapes.iMeta · 2026Review
- 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
- Diagnoses of double heterozygous NF1 variants and dual RASopathy.Molecular and cellular pediatrics · 2026Review
78 more citing papers are in PubMed but not listed here.
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Authors and funding
53 authors at 20 institutions in 15 countries.
Funding
Abstract
backgroundLack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics.
methodsWe implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage.
resultsWe detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions.
conclusionTogether, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics.
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