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

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 Details

Journal
The American Journal of Human Genetics
Published
2026-01-21
DOI
https://doi.org/10.1016/j.ajhg.2025.12.015
Primary Topic
Epilepsy research and treatment
Type
article
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article

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

Gyubin Jang, Heba Ragab Morsy, Zahra Firoozfar, Annarita Scardamaglia et al.
The American Journal of Human Genetics
Epilepsy research and treatment
article

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

Gyubin Jang, Heba Ragab Morsy, Zahra Firoozfar, Annarita Scardamaglia, Vehap Topçu, Eyyüp Üçtepe, Mahmoud M. Noureldeen, Haytham Hussien, Ibrahim M. Abdelrazek, Hesham Aldhalaan, Eleanor Self, Hyeonho Kim, Shahryar Alavi, Fateme Molavi, Tarek I. Omar, Jana Vandrovocova, Reza Maarofian, Vicente A. Yépez, Marwa Abd Elmaksoud, Maha S. Zaki, Ebtessam Abdalla, Stephanie Efthymiou, Javeria Raza Alvi, Mary M. Reilly, Joseph G. Gleeson, Reza Alibakhshi, Bader Alhaddad, Raidah Saleem Albaradie, Ji Won Um, David Murphy, Khadijah Bakur, Henry Houlden, Ehab Salah Showki Tous, Hanifenur Mancilar, Jaewon Ko, Tipu Sultan, Mariasavina Severino, Fowzan S. Alkuraya, Hasnaa M. Elbendary, Ahmet Yesilyurt
article en

Abstract

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.

The American Journal of Human GeneticsVol. 113(2)
Beni-Suef University (EG), Alfaisal University (SA), Punjab Institute of Cardiology (PK), Queen Mary University of London (GB), Kharazmi University (IR), Daegu Gyeongbuk Institute of Science and Technology (KR), Istituto Giannina Gaslini (IT), King Fahad Specialist Hospital (SA), Helmholtz Zentrum München (DE), King Fahd Security College (SA), Acıbadem University (TR), University of California San Diego (US), Kermanshah University of Medical Sciences (IR), Saudi Heart Association (SA), Al-Sabah Hospital (KW), National Research Centre (EG), MRC Prion Unit (GB), National Hospital for Neurology and Neurosurgery (GB), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Acıbadem Adana Hospital (TR), The Queen's Medical Research Institute (GB), University College London (GB), Technical University of Munich (DE), Alexandria University (EG)
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Epilepsy research and treatment
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