ArticleNPJ genomic medicine2021
Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies.
Article in NPJ genomic medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 28 citations in OpenAlex.
- Missense variants in KATNA1 alter microtubule dynamics and underlie dominant macular dystrophy.Research square · 2026Article
- A global survey of systems biology-based predictions of gene-rare disease associations to enhance new diagnoses.Scientific reports · 2026Article
- Enhancing Molecular Diagnostic Accuracy in Genetic Eye Disorders Through a Personalized Re-Evaluation Strategy.Investigative ophthalmology & visual science · 2026Article
- Functional Validation of a Novel Deep IntronicThe application of clinical genetics · 2026Article
- Exploring the strengths and limitations of AI-driven variant prioritization versus manual curation in inborn errors of immunity.Frontiers in genetics · 2026Article
- Article
- New genetic diagnoses for inherited retinal dystrophies by integrating splicing tools into NGS pipelines.NPJ genomic medicine · 2025Article
- Canadian College of Medical Geneticists: clinical practice advisory document - responsibility to recontact for reinterpretation of clinical genetic testing.Journal of medical genetics · 2024Article
- Article
- Reclassification of Variants Following Renal Genetics Testing: Uncommon Yet Impactful for Diagnosis and Management.Kidney international reports · 2024Article
- The Clinical Findings, Pathogenic Variants, and Gene Therapy Qualifications Found in a Leber Congenital Amaurosis Phenotypic Spectrum Patient Cohort.International journal of molecular sciences · 2024Article
- An overview of actionable and potentially actionable TSC1 and TSC2 germline variants in an online Database.Genetics and molecular biology · 2024Article
- Familial co-segregation and the emerging role of long-read sequencing to re-classify variants of uncertain significance in inherited retinal diseases.NPJ genomic medicine · 2023Article
- AJCEM case reports · 2023Article
- Article
- Reclassifying variations of unknown significance in diseases affecting Saudi Arabia's population reveal new associations.Frontiers in genetics · 2023Article
- Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine.Frontiers in medicine · 2023Review
- Five years' experience of the clinical exome sequencing in a Spanish single center.Scientific reports · 2022Article
- Aggregated Genomic Data as Cohort-Specific Allelic Frequencies can Boost Variants and Genes Prioritization in Non-Solved Cases of Inherited Retinal Dystrophies.International journal of molecular sciences · 2022Article
- New Developments and Possibilities in Reanalysis and Reinterpretation of Whole Exome Sequencing Datasets for Unsolved Rare Diseases Using Machine Learning Approaches.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Inherited retinal dystrophies (IRD) are a highly heterogeneous group of rare diseases with a molecular diagnostic rate of >50%. Reclassification of variants of uncertain significance (VUS) poses a challenge for IRD diagnosis. We collected 668 IRD cases analyzed by our geneticists using two different clinical exome-sequencing tests. We identified 114 unsolved cases pending reclassification of 125 VUS and studied their genomic, functional, and laboratory-specific features, comparing them to pathogenic and likely pathogenic variants from the same cohort (N = 390). While the clinical exome used did not show differences in diagnostic rate, the more IRD-experienced geneticist reported more VUS (p = 4.07e-04). Significantly fewer VUS were reported in recessive cases (p = 2.14e-04) compared to other inheritance patterns, and of all the genes analyzed, ABCA4 and IMPG2 had the lowest and highest VUS frequencies, respectively (p = 3.89e-04, p = 6.93e-03). Moreover, few frameshift and stop-gain variants were found to be informed VUS (p = 6.73e-08 and p = 2.93e-06). Last, we applied five pathogenicity predictors and found there is a significant proof of deleteriousness when all score for pathogenicity in missense variants. Altogether, these results provided input for a set of rules that correctly reclassified ~70% of VUS as pathogenic in validation datasets. Disease- and setting-specific features influence VUS reporting. Comparison with pathogenic and likely pathogenic variants can prioritize VUS more likely to be reclassified as causal.
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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.