ArticleInvestigative ophthalmology & visual science2020
Phenotype Driven Analysis of Whole Genome Sequencing Identifies Deep Intronic Variants that Cause Retinal Dystrophies by Aberrant Exonization.
Article in Investigative ophthalmology & visual science, 2020. 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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17 citing papers in PubMed, 27 citations in OpenAlex.
- Identification and functional validation of a novel disease-causing variant in the noncoding region of NYX.Acta ophthalmologica · 2026Article
- A novel phenotype-guided genome analysis pipeline for variant discovery.NPJ genomic medicine · 2026Article
- Comprehensive functional splicing analysis of non-canonical CNGB3 variants using in vitro minigene splice assays.The Journal of pathology · 2025Article
- Autosomal-dominant macular dystrophy linked to a chromosome 17 tandem duplication.JCI insight · 2024Article
- Review
- Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies.Human molecular genetics · 2023Article
- The Current State of Genetic Testing Platforms for Inherited Retinal Diseases.Ophthalmology. Retina · 2022Article
- Confirmation of a Phenotypic Entity forGenes · 2022Article
- Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases.NPJ genomic medicine · 2021Article
- Deciphering the genetic architecture and ethnographic distribution of IRD in three ethnic populations by whole genome sequence analysis.PLoS genetics · 2021Article
- TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study.American journal of medical genetics. Part A · 2021Article
- Next-Generation Sequencing Applications for Inherited Retinal Diseases.International journal of molecular sciences · 2021Review
- A New Mouse Model for Complete Congenital Stationary Night Blindness Due toInternational journal of molecular sciences · 2021Article
- X-Linked Retinitis Pigmentosa Caused by Non-Canonical Splice Site Variants inInternational journal of molecular sciences · 2021Article
- Recent Advances in the Clinical Application of Next-Generation Sequencing.Pediatric gastroenterology, hepatology & nutrition · 2021Review
- Updating the Genetic Landscape of Inherited Retinal Dystrophies.Frontiers in cell and developmental biology · 2021Article
- Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing.Frontiers in genetics · 2021Article
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Authors and funding
19 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Purpose: To demonstrate the effectiveness of combining retinal phenotyping and focused variant filtering from genome sequencing (GS) in identifying deep intronic disease causing variants in inherited retinal dystrophies. Methods: Affected members from three pedigrees with classical enhanced S-cone syndrome (ESCS; Pedigree 1), congenital stationary night blindness (CSNB; Pedigree 2), and achromatopsia (ACHM; Pedigree 3), respectively, underwent detailed ophthalmologic evaluation, optical coherence tomography, and electroretinography. The probands underwent panel-based genetic testing followed by GS analysis. Minigene constructs (NR2E3, GPR179 and CNGB3) and patient-derived cDNA experiments (NR2E3 and GPR179) were performed to assess the functional effect of the deep intronic variants. Results: The electrophysiological findings confirmed the clinical diagnosis of ESCS, CSNB, and ACHM in the respective pedigrees. Panel-based testing revealed heterozygous pathogenic variants in NR2E3 (NM_014249.3; c.119-2A>C; Pedigree 1) and CNGB3 (NM_019098.4; c.1148delC/p.Thr383Ilefs*13; Pedigree 3). The GS revealed heterozygous deep intronic variants in Pedigrees 1 (NR2E3; c.1100+1124G>A) and 3 (CNGB3; c.852+4751A>T), and a homozygous GPR179 variant in Pedigree 2 (NM_001004334.3; c.903+343G>A). The identified variants segregated with the phenotype in all pedigrees. All deep intronic variants were predicted to generate a splice acceptor gain causing aberrant exonization in NR2E3 [89 base pairs (bp)], GPR179 (197 bp), and CNGB3 (73 bp); splicing defects were validated through patient-derived cDNA experiments and/or minigene constructs and rescued by antisense oligonucleotide treatment. Conclusions: Deep intronic mutations contribute to missing heritability in retinal dystrophies. Combining results from phenotype-directed gene panel testing, GS, and in silico splice prediction tools can help identify these difficult-to-detect pathogenic deep intronic variants.
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