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Morsy, H.* ; Kim, H.* ; Jang, G.* ; Zaki, M.S.* ; Severino, M.* ; Abdelrazek, I.M.* ; Hussien, H.* ; Self, E.* ; Albaradie, R.S.* ; Bakur, K.* ; Firoozfar, Z.* ; Efthymiou, S.* ; Noureldeen, M.M.* ; Nabil, A.* ; Alvi, J.R.* ; Molavi, F.* ; Alavi, S.* ; Alibakhshi, R.* ; Topcu, V.* ; Mancilar, H.* ; Uctepe, E.* ; Yesilyurt, A.* ; Aldhalaan, H.* ; Showki Tous, E.S.* ; Alhaddad, B.* ; Elbendary, H.M.* ; Scardamaglia, A.* ; Murphy, D.* ; Yépez, V.A.* ; Gagneur, J. ; Omar, T.I.* ; Abd Elmaksoud, M.* ; Vandrovocova, J.* ; Abdalla, E.* ; Reilly, M.M.* ; Sultan, T.* ; Alkuraya, F.S.* ; Gleeson, J.G.* ; Um, J.W.* ; Houlden, H.* ; Ko, J.* ; Maarofian, R.*

MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy.

Am. J. Hum. Genet. 113, 380-391 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
MDGA2 encodes a membrane-associated protein that is critical for regulating glutamatergic synapse development, modulating neuroligins (Nlgns), and maintaining excitatory-inhibitory synaptic balance. While MDGA2 functions have been extensively studied in murine and cellular models, its association with human developmental disorders has yet to be established. Through exome sequencing, we identified seven distinct homozygous loss-of-function variants in MDGA2 in nine individuals from seven consanguineous families, all presenting with developmental and epileptic encephalopathy (DEE). Clinically, these individuals exhibited a consistent phenotype including infantile hypotonia, severe neurodevelopmental delay, intractable seizures, along with distinct dysmorphic features. Neuroimaging findings included delayed/incomplete myelination, early-onset brain atrophy, white-matter thinning, basal ganglia volume loss, and small hippocampi. Functional studies of three representative nonsense variants revealed impaired MDGA2 membrane trafficking, disrupted Nlgn1 interaction, and perturbed MDGA2-mediated excitatory synaptic functions in mammalian expression systems and cultured hippocampal neurons. Our findings support the involvement of MDGA2 in a subtype of autosomal-recessive DEE. This not only underscores a loss-of-function pathogenic mechanism but also highlights the previously unrecognized role of MDGA2 in human synaptic development and regulation, significantly expanding our understanding of the genetic architecture of DEEs.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mdga2 ; Epileptic Encephalopathy ; Excitatory Synapse ; Excitatory-inhibitory Balance ; Neurodevelopmental Disorder ; Neuroligin ; Synaptic Suppression
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 113, Issue: 2, Pages: 380-391 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants Victoria Brain Bank
Fidelity Trust
EAN
Michael J. Fox Foundation (MJFF)
FARA
National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR-BRC)
MSA Trust
MRC
GERF-STDF
NRF - Ministry of Science and ICT
National Research Foundation of Korea (NRF) - Ministry of Science and ICT
UCL Global Engagement Fund scheme
Wellcome Trust
Rosetrees Trust
NIH NeuroBioBank
Dolby Family Fund

Cerebral Palsy Alliance
Guarantors of Brain
DFG
Parkinson's Foundation
European Union
Parkinson Disease Society
Deutsche Forschungsgemeinschaft (DFG
MSA Coalition
MRC Brainbank Network
Alzheimer's Research UK (ARUK)
Queen Square BrainBank
Nile of Hope Hospital for Congenital Anomalies, Alexandria, Egypt