ArticleAmerican journal of human genetics2023
Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders.
Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 57 citations in OpenAlex.
- An episignature informed systematic analysis to ascertain the clinical significance and consequences of CHD8 missense variants.European journal of human genetics : EJHG · 2026Article
- Fibroblast Transcriptomics in Molecular Diagnostics of a Comprehensive Dystonia Cohort.Annals of neurology · 2026Article
- HiFi long-read RNA sequencing enhances clinical diagnostics in rare disorders.European journal of human genetics : EJHG · 2026Article
- Homozygous SGCB splice-site variant causes isolated dilated cardiomyopathy through sarcoglycan complex destabilization in East Asians.The Journal of clinical investigation · 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
- Two siblings with CCDC32-related cardiofacioneurodevelopmental syndrome diagnosed by clinical RNA-sequencing and review of literature.European journal of human genetics : EJHG · 2026Review
- 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
- Resolving non‑coding splice‑altering variants using an integrative genomic and transcriptomic workflow: application to FOXP1.Human genomics · 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
- Long-read DNA and RNA sequencing reveal an intronic retrotransposon insertion in TCOF1 causing Treacher Collins syndrome.HGG advances · 2026Article
- Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia.American journal of human genetics · 2026Article
- A de novo missense variant in MIDEAS results in increased deacetylase activity of the MiDAC HDAC complex causing a neurodevelopmental syndrome.Nature communications · 2025Article
- VPS13D-Related Disorders: Description of New Variant and Phenotypic Spectrum Based on Age of Onset.Cerebellum (London, England) · 2025Article
- A clinical and genotype-phenotype analysis of MACF1 variants.American journal of human genetics · 2025Article
- Clinical utility of DNA-methylation signatures in routine diagnostics for neurodevelopmental disorders.European journal of human genetics : EJHG · 2025Article
- Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort.Genome medicine · 2025Article
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Authors and funding
29 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers. Analysis was performed by a user-friendly web application, and candidate pathogenic transcriptional events were confirmed by secondary assays. We identified intragenic deletions, monoallelic expression, and pseudoexonic insertions but also synonymous and non-synonymous variants with deleterious effects on transcription, increasing the diagnostic yield for NDDs by 13%. We found that cycloheximide treatment and exonic/intronic Z score analysis increased detection and resolution of aberrant splicing. Importantly, in one individual mis-splicing was found in a candidate gene nearly matching the individual's specific phenotype. However, pathogenic splicing occurred in another neuronal-expressed gene and provided a molecular diagnosis, stressing the need to customize RNA-seq. Lastly, our web browser application allowed custom analysis settings that facilitate diagnostic application and ranked pathogenic transcripts as top candidates. Our results demonstrate that RNA-seq is a complementary method in the genomic diagnosis of NDDs and, by providing accessible analysis with improved sensitivity, our transcriptome analysis approach facilitates wider implementation of RNA-seq in routine genome diagnostics.
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