Show Notes
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/
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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
- metadata issues found: 0
Metadata Audited:
- article_doi
- article_title
- article_journal
- license
Factual Items Audited:
- MDGA2 homozygous loss-of-function variants identified in nine individuals from seven consanguineous families
- MDGA2 variants cause trafficking impairment and loss of surface expression with disrupted Nlgn1 interaction
- MDGA2 waives suppression of excitatory synapses in LoF variants; WT MDGA2 suppresses excitatory synapse numbers
- Electrophysiology shows MDGA2 WT reduces mEPSC frequency and AMPAR/NMDAR EPSCs; LoF variants fail to alter synaptic function
- DEE phenotype with early-onset seizures, severe developmental delay, dysmorphic features; brain MRI shows delayed myelination and early brain atrophy
- Ketogenic diet produced partial seizure control in two individuals (P4 and P5B)
QC result: Pass.
