ArticleAmerican journal of human genetics2021
Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed.
- Kidney Transcriptome Sequencing Improves Molecular Diagnosis and Reveals Splicing Complexity Across the Alport Spectrum.Kidney international reports · 2026Article
- Rapid minigene workflow for functional reclassification of splicing variants in hereditary cancer diagnostics.Journal of medical genetics · 2026Article
- Uncultured Amniocytes Enable Rapid and Clinically Informative Prenatal RNA Sequencing for Genetic Diagnosis.International journal of molecular sciences · 2026Article
- 'Missing' disease-causing variants in Alport syndrome.Nature reviews. Nephrology · 2026Review
- Variant-specific RNA testing resolves variants of uncertain significance in exome testing.BMC genomics · 2026Article
- Utility of Targeted RNA Analysis in Neurogenetic Disorders.Neurology. Genetics · 2026Article
- Expanding the genetic landscape of inherited metabolic diseases using long-read sequencing and transcriptomic profiling.European journal of human genetics : EJHG · 2026Article
- Genome and transcriptome sequencing reveal pathogenic activation of a pseudoexon inGenetics in medicine open · 2026Article
- Case Report: PTCH1 splice-site mutation and sonidegib treatment in Gorlin-Goltz syndrome: clinical insights from a family case study.Frontiers in medicine · 2026Article
- Molecular characterization of a novel synonymous variant in a Mexican patient with Pompe disease.Molecular genetics and metabolism reports · 2025Article
- A Plot Twist: When RNA Yields Unexpected Findings in Paired DNA-RNA Germline Genetic Testing.Genes · 2025Article
- Genome-wide functional annotation and interpretation of splicing variants: toward RNA-targeted therapies.Journal of human genetics · 2025Review
- Assessing the Functional Significance of Novel and Rare Variants of theInternational journal of molecular sciences · 2025Article
- RNA-seq Splicing Profile of theCancers · 2025Article
- Advancements in Prenatal Genetic Screening and Testing: Emerging Technologies and Evolving Applications.Diagnostics (Basel, Switzerland) · 2025Review
- Decipher RNA isoform combinations from minigene splicing assays and massive parallel sequencing with MAGIC.Bioinformatics (Oxford, England) · 2025Article
- RNA-sequencing unveils FLT4 splice site variants in variable congenital heart disease.European journal of human genetics : EJHG · 2025Article
- Beyond genomics: using RNA-seq from dried blood spots to unlock the clinical relevance of splicing variation in a diagnostic setting.European journal of human genetics : EJHG · 2025Article
- Identifying six single nucleotide variants in the COL17A1 gene that alter RNA splicing: database analysis and minigene assays.Scientific reports · 2025Article
- Navigating Genetic Testing in Nephrology: Options and Decision-Making Strategies.Kidney international reports · 2025Review
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10 authors.
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Abstract
The complexities of gene expression pose challenges for the clinical interpretation of splicing variants. To better understand splicing variants and their contribution to hereditary disease, we evaluated their prevalence, clinical classifications, and associations with diseases, inheritance, and functional characteristics in a 689,321-person clinical cohort and two large public datasets. In the clinical cohort, splicing variants represented 13% of all variants classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUSs). Most splicing variants were outside essential splice sites and were classified as VUSs. Among all individuals tested, 5.4% had a splicing VUS. If RNA analysis were to contribute supporting evidence to variant interpretation, we estimated that splicing VUSs would be reclassified in 1.7% of individuals in our cohort. This would result in a clinically significant result (i.e., P/LP) in 0.1% of individuals overall because most reclassifications would change VUSs to likely benign. In ClinVar, splicing VUSs were 4.8% of reported variants and could benefit from RNA analysis. In the Genome Aggregation Database (gnomAD), splicing variants comprised 9.4% of variants in protein-coding genes; most were rare, precluding unambiguous classification as benign. Splicing variants were depleted in genes associated with dominant inheritance and haploinsufficiency, although some genes had rare variants at essential splice sites or had common splicing variants that were most likely compatible with normal gene function. Overall, we describe the contribution of splicing variants to hereditary disease, the potential utility of RNA analysis for reclassifying splicing VUSs, and how natural variation may confound clinical interpretation of splicing variants.
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