ArticleHuman mutation2017
Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance.
Article in Human mutation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 44 citations in OpenAlex.
- Identification and splicing assessment of a novel homozygous CFAP65 splice-site variant associated with oligozoospermia and complete asthenozoospermia.BMC medical genomics · 2026Article
- Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.Molecular medicine (Cambridge, Mass.) · 2026Article
- Functional and structural characterization ofFrontiers in endocrinology · 2026Article
- Functional Validation of a Novel Deep IntronicThe application of clinical genetics · 2026Article
- Hidden Splicing Variants in Inherited Retinal Degeneration: Discovery and Functional Insight.Investigative ophthalmology & visual science · 2025Article
- Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays.Biomedicines · 2025Article
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- Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment.Human genetics · 2022Article
- Frequency and phenotypic characteristics of RPE65 mutations in the Chinese population.Orphanet journal of rare diseases · 2021Article
- Identification of Deep-Intronic Splice Mutations in a Large Cohort of Patients With Inherited Retinal Diseases.Frontiers in genetics · 2021Article
- Noncoding mutation inMolecular vision · 2021Article
- Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in theFrontiers in genetics · 2020Article
- Seven novel variants expand the spectrum ofMolecular vision · 2019Article
- Spectrum, frequency, and genotype-phenotype of mutations inMolecular vision · 2019Article
- Relative frequency of inherited retinal dystrophies in Brazil.Scientific reports · 2018Article
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Authors and funding
20 authors at 7 institutions in 4 countries.
Funding
Abstract
The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here, we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS) that are disrupting splicing in a known IRD gene by means other than affecting the canonical dinucleotide splice site. Three in silico splice-affecting variant predictors were leveraged to annotate and prioritize variants for splicing functional validation. An in vitro minigene system was used to assay each variant's effect on splicing. Starting with 745 IRD patients lacking a confident molecular diagnosis, we validated 23 VUS as splicing variants that likely explain disease in 26 patients. Using our results, we optimized in silico score cutoffs to guide future variant interpretation. Variants that alter base pairs other than the canonical GT-AG dinucleotide are often not considered for their potential effect on RNA splicing but in silico tools and a minigene system can be utilized for the prioritization and validation of such splice-disrupting variants. These variants can be overlooked causes of human disease but can be identified using conventional exon sequencing with proper interpretation guidelines.
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