High-throughput behavioural phenotyping of 25 C. elegans disease models including patient-specific mutations
Author(s)
Type
Journal Article
Abstract
Background
Genetic diagnosis is fast and cheap, challenging our capacity to evaluate the functional impact of novel disease-causing variants or identify potential therapeutics. Model organisms including C. elegans present the possibility of systematically modelling genetic diseases, yet robust, high‐throughput methods have been lacking.
Results
Here we show that automated multi‐dimensional behaviour tracking can detect phenotypes in 25 new C. elegans disease models spanning homozygous loss‐of‐function alleles and patient‐specific single‐amino‐acid substitutions. We find that homozygous loss‐of‐function (LoF) mutants across diverse genetic pathways (including BORC, FLCN, and FNIP‐2) exhibit strong, readily detectable abnormalities in posture, locomotion, and stimulus responses compared to wild‐type animals. An smc-3 mutant strain—modelled by introducing a patient‐identified missense change—exhibited developmental anomalies and distinct behavioural profiles even though complete loss of SMC‐3 is lethal. In contrast, patient-derived missense mutations in another essential gene, tnpo-2, did not show a strong phenotype initially but it could be “sensitized” chemically (e.g., with aldicarb), potentially facilitating future drug screens.
Conclusions
Our findings show that scalable behavioural phenotyping can capture a wide range of mutant effects—from strong to subtle—in patient‐avatar worm lines. We anticipate that this standardized approach will enable systematic drug repurposing for rare genetic disorders as new disease variants are discovered.
Genetic diagnosis is fast and cheap, challenging our capacity to evaluate the functional impact of novel disease-causing variants or identify potential therapeutics. Model organisms including C. elegans present the possibility of systematically modelling genetic diseases, yet robust, high‐throughput methods have been lacking.
Results
Here we show that automated multi‐dimensional behaviour tracking can detect phenotypes in 25 new C. elegans disease models spanning homozygous loss‐of‐function alleles and patient‐specific single‐amino‐acid substitutions. We find that homozygous loss‐of‐function (LoF) mutants across diverse genetic pathways (including BORC, FLCN, and FNIP‐2) exhibit strong, readily detectable abnormalities in posture, locomotion, and stimulus responses compared to wild‐type animals. An smc-3 mutant strain—modelled by introducing a patient‐identified missense change—exhibited developmental anomalies and distinct behavioural profiles even though complete loss of SMC‐3 is lethal. In contrast, patient-derived missense mutations in another essential gene, tnpo-2, did not show a strong phenotype initially but it could be “sensitized” chemically (e.g., with aldicarb), potentially facilitating future drug screens.
Conclusions
Our findings show that scalable behavioural phenotyping can capture a wide range of mutant effects—from strong to subtle—in patient‐avatar worm lines. We anticipate that this standardized approach will enable systematic drug repurposing for rare genetic disorders as new disease variants are discovered.
Date Issued
2025-12-01
Date Acceptance
2025-07-31
Citation
BMC Biology, 2025, 23
ISSN
1741-7007
Publisher
BMC
Journal / Book Title
BMC Biology
Volume
23
Issue
1
Copyright Statement
© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41013606
PII: 10.1186/s12915-025-02368-8
Subjects
Allelic variant
AUTOPHAGY
Biology
BORC
Caenorhabditis elegans
Disease modelling
FLCN
GENE
High-throughput phenotyping
Life Sciences & Biomedicine
Life Sciences & Biomedicine - Other Topics
LYSOSOMES
MECHANISMS
Multidimensional behaviour
NECROTIC CELL-DEATH
Patient avatar
PROTEIN
RISK
Science & Technology
TRAFFICKING
Publication Status
Published
Coverage Spatial
England
Article Number
281
Date Publish Online
2025-09-26