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In Vivo Modeling of the Morbid Human Genome using Danio rerio
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Phenotypic diversity is caused by non-linear genetic interactions between two SNAREopathy genes
Jovana Kovačević1, Sébastien Houy2, Johny Pires1
1Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, De Boelelaan 1085, Amsterdam, 1081 HV, the Netherlands.
Molecular Psychiatry
|March 4, 2026
Summary
Genetic interactions explain symptom diversity in brain disorders. Combining mutations in interacting genes, like those causing SNAREopathies, leads to varied outcomes, from severe seizures to no symptoms, in mouse models.
Area of Science:
- Neurogenetics
- Systems Neuroscience
- Developmental Biology
Background:
- Large effect mutations in single genes cause brain disorders with unexplained symptom diversity.
- SNAREopathies, neurodevelopmental disorders from variations in secretion genes, exhibit significant phenotypic variability.
- Existing research lacks explanation for the wide range of symptoms in patients with the same mutation.
Purpose of the Study:
- To investigate if non-linear genetic interactions between functionally related genes explain phenotypic diversity in SNAREopathies.
- To compare phenotypic diversity in single and double mutant mouse models at multiple biological levels.
- To develop a theoretical framework for understanding genetic interaction-driven symptom diversity.
Main Methods:
- Utilized validated mouse models for Stxbp1 and Snap25 mutations, key genes in SNAREopathies.
- Generated single and double mutant mice to assess genetic interaction effects.
- Evaluated phenotypes across synaptic, network, system, and behavioral levels, including EEG, motor activity, and cFos staining.
Main Results:
- Single mutants (Stxbp1, Snap25) showed EEG and motor abnormalities but no seizures.
- Double mutants displayed extreme seizure phenotype diversity, ranging from lethal generalized seizures to no observable abnormalities.
- Surviving double mutants did not exhibit more severe phenotypes than single mutants at synaptic, network, or behavioral levels.
Conclusions:
- Haploinsufficiency in two interacting genes leads to extreme systems-level phenotypic diversity.
- Genetic interactions, particularly non-linear ones, are a key driver of symptom variability in neurodevelopmental disorders.
- Findings provide a proof of concept for how modifying genes in a patient's genome can enhance phenotypic diversity, applicable to human patients.
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