ArticleAmerican journal of human genetics2017
Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites.
Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 78 citations in OpenAlex.
- G970R-CFTR Mutation (c.2908G>C) Results Predominantly in a Splicing Defect.Clinical and translational science · 2021Trial
- A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants.American journal of human genetics · 2019Trial
- Elexacaftor/Tezacaftor/Ivacaftor Supports Treatment for CF with ΔI1023-V1024-CFTR.International journal of molecular sciences · 2025Article
- Identified five variants in CFTR gene that alter RNA splicing by minigene assay.Frontiers in genetics · 2025Article
- Integrative Analysis of Germline Rare Variants in Clear and Non-clear Cell Renal Cell Carcinoma.European urology open science · 2024Article
- The genome of the black-footed cat: Revealing a rich natural history and urgent conservation priorities for small felids.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Molecular and functional correction of a deep intronic splicing mutation inMolecular therapy. Methods & clinical development · 2023Article
- Protospacer modification improves base editing of a canonical splice site variant and recovery of CFTR function in human airway epithelial cells.Molecular therapy. Nucleic acids · 2023Article
- Introme accurately predicts the impact of coding and noncoding variants on gene splicing, with clinical applications.Genome biology · 2023Article
- Challenges Related to the Use of Next-Generation Sequencing for the Optimization of Drug Therapy.Handbook of experimental pharmacology · 2023Article
- Telomere-mediated lung disease.Physiological reviews · 2022Review
- Downstream Alternate Start Site Allows N-Terminal Nonsense Variants to Escape NMD and Results in Functional Recovery by Readthrough and Modulator Combination.Journal of personalized medicine · 2022Article
- Splicing mutations in the CFTR gene as therapeutic targets.Gene therapy · 2022Review
- Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders.Scientific reports · 2021Article
- What's Wrong in a Jump? Prediction and Validation of Splice Site Variants.Methods and protocols · 2021Review
- The genetics of mitochondrial disease: dissecting mitochondrial pathology using multi-omic pipelines.The Journal of pathology · 2021Review
- A deep learning approach to identify gene targets of a therapeutic for human splicing disorders.Nature communications · 2021Article
- Synonymous variants that disrupt messenger RNA structure are significantly constrained in the human population.GigaScience · 2021Article
- Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing.Frontiers in genetics · 2021Article
- Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis.Chest · 2020Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
We developed a variant-annotation method that combines sequence-based machine-learning classification with a context-dependent algorithm for selecting splice variants. Our approach is distinctive in that it compares the splice potential of a sequence bearing a variant with the splice potential of the reference sequence. After training, classification accurately identified 168 of 180 (93.3%) canonical splice sites of five genes. The combined method, CryptSplice, identified and correctly predicted the effect of 18 of 21 (86%) known splice-altering variants in CFTR, a well-studied gene whose loss-of-function variants cause cystic fibrosis (CF). Among 1,423 unannotated CFTR disease-associated variants, the method identified 32 potential exonic cryptic splice variants, two of which were experimentally evaluated and confirmed. After complete CFTR sequencing, the method found three cryptic intronic splice variants (one known and two experimentally verified) that completed the molecular diagnosis of CF in 6 of 14 individuals. CryptSplice interrogation of sequence data from six individuals with X-linked dyskeratosis congenita caused by an unknown disease-causing variant in DKC1 identified two splice-altering variants that were experimentally verified. To assess the extent to which disease-associated variants might activate cryptic splicing, we selected 458 pathogenic variants and 348 variants of uncertain significance (VUSs) classified as high confidence from ClinVar. Splice-site activation was predicted for 129 (28%) of the pathogenic variants and 75 (22%) of the VUSs. Our findings suggest that cryptic splice-site activation is more common than previously thought and should be routinely considered for all variants within the transcribed regions of genes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.