ArticleHuman molecular genetics2022
Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) in Caenorhabditis elegans.
Article in Human molecular genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Interpreting the functional impact of genetic variants: The need for context qualifiers.American journal of human genetics · 2026Review
- Article
- Kinesins inOpen biology · 2025Review
- C. elegans: An elegant experimental system for the study of cilia biology.Seminars in cell & developmental biology · 2025Review
- Functional Testing of Human Disease Missense Variants inKidney international reports · 2025Article
- Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions.Nature communications · 2025Article
- Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis.Nature communications · 2025Article
- Functional analysis ofGenetics in medicine open · 2025Article
- The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients.Journal of human genetics · 2024Article
- The Extraordinary Phenotypic and Genetic Variability of Retinal and Macular Degenerations: The Relevance to Therapeutic Developments.Cold Spring Harbor perspectives in medicine · 2024Review
- Matching variants for functional characterization of genetic variants.G3 (Bethesda, Md.) · 2023Article
- Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics.Molecular aspects of medicine · 2023Review
- Back to the future through the wormhole: Caenorhabditis elegans as a preclinical model.Disease models & mechanisms · 2023Article
- Tracking N- and C-termini of C. elegans polycystin-1 reveals their distinct targeting requirements and functions in cilia and extracellular vesicles.PLoS genetics · 2022Article
- From bugs to bedside: functional annotation of human genetic variation for neurological disorders using invertebrate models.Human molecular genetics · 2022Article
- Article
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6 authors at 3 institutions in 2 countries.
Funding
Abstract
Better methods are required to interpret the pathogenicity of disease-associated variants of uncertain significance (VUS), which cannot be actioned clinically. In this study, we explore the use of an animal model (Caenorhabditis elegans) for in vivo interpretation of missense VUS alleles of TMEM67, a cilia gene associated with ciliopathies. CRISPR/Cas9 gene editing was used to generate homozygous knock-in C. elegans worm strains carrying TMEM67 patient variants engineered into the orthologous gene (mks-3). Quantitative phenotypic assays of sensory cilia structure and function (neuronal dye filling, roaming and chemotaxis assays) measured how the variants impacted mks-3 gene function. Effects of the variants on mks-3 function were further investigated by looking at MKS-3::GFP localization and cilia ultrastructure. The quantitative assays in C. elegans accurately distinguished between known benign (Asp359Glu, Thr360Ala) and known pathogenic (Glu361Ter, Gln376Pro) variants. Analysis of eight missense VUS generated evidence that three are benign (Cys173Arg, Thr176Ile and Gly979Arg) and five are pathogenic (Cys170Tyr, His782Arg, Gly786Glu, His790Arg and Ser961Tyr). Results from worms were validated by a genetic complementation assay in a human TMEM67 knock-out hTERT-RPE1 cell line that tests a TMEM67 signalling function. We conclude that efficient genome editing and quantitative functional assays in C. elegans make it a tractable in vivo animal model for rapid, cost-effective interpretation of ciliopathy-associated missense VUS alleles.
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