Loss of the transcription factor NEUROD2 causes a spectrum of neurobehavioral phenotypes in mice and humans

The neuronal transcription factor NeuroD2 has recently been associated with early encephalopathic epilepsy 1 and genome-wide association studies (GWAS) have suggested that it might be a candidate for neuropsychiatric disorders 2. We set out to understand the function of NeuroD2 in cortex development and behavior and found that deleting this factor in mice results in altered migration, laminar positioning, structural synaptic maturation and physiology of cortical projection neurons (CPNs), as well as in differential expression of genes associated with neuronal excitability, synaptic transmission and neurodevelopmental disorders. These cellular and molecular defects were correlated with behavioral defects, namely locomotor hyperactivity, altered social interest and social memory, stereotypic behaviors and spontaneous seizures. Informed by these neurobehavioral features in mouse mutants, we identified individuals with de novo and familial heterozygous missense mutations in NEUROD2 or copy number variations involving NEUROD2, who shared clinical features such as intellectual disability (ID) and autism spectrum disorder (ASD), with sometimes hyperactivity and epilepsy. In vitro functional analyses showed that NEUROD2 missense mutations identified in a non-consanguineous family and a sporadic case were both pathogenic. Our study demonstrates that loss-of-function mutations in NEUROD2 cause a spectrum of neurobehavioral phenotypes including ID and ASD.