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 the balance between excitatory and inhibitory synapses. Although MDGA2 has been extensively studied in murine and cellular models, its association with human developmental disorders has not been established to date. Through exome sequencing we identified six distinct homozygous loss-of-function MDGA2 variants in eight individuals from six consanguineous families, all presenting with developmental and epileptic encephalopathy (DEE). Clinically, these patients exhibited infantile hypotonia, severe neurodevelopmental delay, intractable seizures, progressive brain atrophy, and consistent dysmorphic features, including high anterior hairline, high-arched eyebrows, broad nasal ridge, tented upper lip, and large, low-set ears. Functional studies of three representative nonsense variants in mammalian expression systems and hippocampal cultured neurons revealed impaired MDGA2 membrane trafficking and disrupted Nlgn1 interaction, leading to defective excitatory synapse formation, synaptic transmission, and synaptic strength. Altogether, our findings definitively establish MDGA2 as a novel gene for autosomal recessive DEE subtype, with the pathogenesis explained by loss-of-function mechanism. This discovery underscores the previously unrecognized role of MDGA2 in human synaptic development and regulation, significantly expanding our understanding of the genetic architecture of DEE.