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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• MDGA2 protein regulates glutamatergic synapse development and synaptic balance.
• Previous studies focused on MDGA2 functions in animal and cellular models.
• MDGA2's role in human developmental disorders was previously unknown.

Purpose of the Study:

• To investigate the association between MDGA2 and human developmental disorders.
• To identify the genetic basis of a specific neurodevelopmental condition.
• To elucidate the functional consequences of MDGA2 loss-of-function in humans.

Main Methods:

• Exome sequencing was used to identify genetic variants in affected individuals.
• Clinical phenotyping and neuroimaging were performed on affected individuals.
• Functional studies assessed the impact of identified MDGA2 variants on protein function in vitro.

Main Results:

• Seven distinct homozygous loss-of-function MDGA2 variants were identified in nine individuals from seven families.
• Affected individuals presented with a consistent phenotype of developmental and epileptic encephalopathy (DEE), hypotonia, severe neurodevelopmental delay, intractable seizures, and dysmorphic features.
• Functional studies confirmed impaired MDGA2 trafficking, disrupted neuroligin interaction, and perturbed synaptic function due to the identified variants.

Conclusions:

• MDGA2 loss-of-function variants are implicated in a subtype of autosomal-recessive DEE.
• This study establishes the critical role of MDGA2 in human synaptic development and regulation.
• The findings expand the understanding of the genetic causes of DEEs.