ArticleGenome medicine2022
A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project.
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 40 papers.
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40 citing papers in PubMed, 53 citations in OpenAlex.
- Kidney Transcriptome Sequencing Improves Molecular Diagnosis and Reveals Splicing Complexity Across the Alport Spectrum.Kidney international reports · 2026Article
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.Nature communications · 2026Article
- The Pathogenicity Analysis of a Hypogonadotropic Hypogonadism Patient With the Novel Variant in the Deep Intronic Region of the PROK2 Gene.Molecular genetics & genomic medicine · 2026Article
- Cardiovascular Genetic Epidemiology in the Genome-Wide Era: From Association Discovery to Mechanistic Dissection and Clinical Translation.Cardiovascular drugs and therapy · 2026Review
- HiFi long-read RNA sequencing enhances clinical diagnostics in rare disorders.European journal of human genetics : EJHG · 2026Article
- Genetic background shapes AI-predicted variant effects.bioRxiv : the preprint server for biology · 2026Article
- IFDlong: a model-based isoform and fusion detector for accurate annotation and quantification of long-read RNA-seq data.Genome biology · 2026Article
- Identification of Intronic Variants inNeurology. Genetics · 2026Article
- Generation of functional noncanonical donor splice sites by +2T variants in breast cancer susceptibility genes: impact on clinical interpretation.The Journal of pathology · 2026Article
- Clinical and Molecular Genetic Study of an Alagille Syndrome Type 1 Case.Advances in experimental medicine and biology · 2026Article
- Cell modeling and rescue of a novel noncoding genetic cause of glycogen storage disease IX.Genetics in medicine open · 2026Article
- Synonymous and non-synonymous variants at splice junctions can disrupt splicing and are frequently linked to disease associated loss of function genes.BMC genomics · 2025Article
- Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.bioRxiv : the preprint server for biology · 2025Article
- Beyond the Exome: The Role of Noncoding and Regulatory Variants in Monogenic Diseases.Current issues in molecular biology · 2025Review
- Type I interferon-mediated autoinflammation in two unrelated patients due to a proximal intronic splice site variant inResearch square · 2025Article
- Early diagnosed Zaki syndrome: identification of two novel WLS variants and a literature review.Italian journal of pediatrics · 2025Review
- New genetic diagnoses for inherited retinal dystrophies by integrating splicing tools into NGS pipelines.NPJ genomic medicine · 2025Article
- Whole-genome Sequencing Association Analysis of Quantitative Platelet Traits in A Large Cohort of β-thalassemia.Genomics, proteomics & bioinformatics · 2025Article
- Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay.Molecular psychiatry · 2025Article
- Systematic identification of disease-causing promoter and untranslated region variants in 8040 undiagnosed individuals with rare disease.Genome medicine · 2025Article
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Authors and funding
20 authors at 9 institutions in 1 country.
Funding
Abstract
backgroundGenomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data.
methodsHere, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon-intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon-intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies.
resultsWe show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed.
conclusionsOverall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases.
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