Show Notes
Morsy H et al., The American Journal of Human Genetics - Exome sequencing identifies homozygous MDGA2 loss-of-function variants in nine individuals and functional neuronal assays show impaired MDGA2 trafficking with disrupted Nlgn1-dependent excitatory synapse regulation causing DEE.
Study Highlights:
Exome sequencing of consanguineous families identified seven distinct homozygous MDGA2 loss-of-function variants in nine individuals with severe developmental and epileptic encephalopathy. Functional evaluation used mammalian expression in HEK293T cells, heterologous synapse-formation assays, cultured hippocampal neurons, and electrophysiology. Representative nonsense variants abolished MDGA2 surface trafficking, disrupted MDGA2–Nlgn1 binding, failed to suppress excitatory synapse density, and did not reduce AMPAR- and NMDAR-mediated synaptic responses. These synaptic deficits imply disruption of excitatory-inhibitory balance, providing a mechanistic link to early-onset intractable seizures and progressive neurodevelopmental impairment.
Conclusion:
Homozygous MDGA2 loss-of-function variants cause an autosomal-recessive developmental and epileptic encephalopathy by impairing MDGA2 trafficking and Nlgn1-dependent suppression of excitatory synapses.
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Reference:
Morsy H, Kim H, Jang G, et al. MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy. The American Journal of Human Genetics. 2026;113:1–12. https://doi.org/10.1016/j.ajhg.2025.12.015
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/
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