Key result
Depdc5 haploinsufficiency in mice promotes cardiac remodeling, suggesting non-ion-channel DEE variants predispose patients to arrhythmias.
This preclinical study suggests that DEPDC5 haploinsufficiency may predispose to cardiac arrhythmias, highlighting a potential non-ion-channel mechanism for cardiac involvement in developmental and epileptic encephalopathies.
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Should not yet change practice for DEPDC5 variant carriers; extends cardiac risk to non-ion-channel epilepsy genes.
These data strengthen the hypothesis that cardiac arrhythmias may contribute to the complex presentation of DEE and expand our previous work showing cardiac arrhythmia in multiple mouse and human channelopathy models to include a model of a non-ion-channel variant. Although this work may have implications for DEPDC5 patients, critical differences between mouse and human cardiac physiology complicate the translation of mouse data to human disease. Essential next steps must include investigation of Depdc5 function in higher vertebrate models that more accurately mimic human physiology, as well as longitudinal patient natural history studies that monitor cardiovascular health, to test the hypothesis that DEE variants resulting in DEPDC5 haploinsufficiency may predispose patients to cardiac arrhythmias.
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Ramos‐Mondragón et al. (2026) studied Depdc5 haploinsufficiency. Depdc5 haploinsufficiency was evaluated on Cardiac remodeling and arrhythmia. A mouse model of Depdc5 haploinsufficiency exhibited cardiac remodeling and arrhythmia, suggesting that non-ion-channel DEE variants may predispose patients to cardiac arrhythmias.
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