277: MDGA2 homozygous loss-of-function variants in developmental and epileptic encephalopathy

Morsy H et al., The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2025.12.015 - 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. Key terms: MDGA2, developmental and epileptic encephalopathy, loss-of-function, neuroligin-1, exome sequencing. 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. Music:Enjoy the music based on this article at the end of the episode. Article title:MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy First author:Morsy H Journal:The American Journal of Human Genetics, Corrected proof. doi:10.1016/j.ajhg.2025.12.015 DOI:10.1016/j.ajhg.2025.12.015 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/mdga2-loss-of-function-dee QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-01. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audit covered the sections describing MDGA2 function in synaptic regulation, genetic basis (LoF variants in consanguineous families), functional assays (trafficking, Nlgn1 interactions, synapse formation, electrophysiology), clinical phenotype (DEE with seizures), and therapeutic angles (ketogenic diet, potential recep- transcript topics: MDGA2 as a brake on Nlgn1 and suppression of excitatory synapses; Genetic basis: homozygous loss-of-function MDGA2 variants in consanguineous families; Functional validation: trafficking and surface expression of MDGA2; Nlgn1 interaction; Synapse formation and electrophysiology: mEPSCs, AMPAR/NMDAR EPSCs; Clinical presentation: DEE phenotype, hypotonia, seizures, dysmorphic features, MRI findings; Therapeutic angles: ketogenic diet effects; potential TRKB/AMPA receptor–related targets QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4-...