Autism spectrum disorders (ASDs) include a variety of developmental brain disorders with clinical findings implicating the dysfunction of the left hemisphere. Here, we generate mice lacking one copy of Sh3rf2, which was detected in ASD patients, to determine whether Sh3rf2 is involved in brain development and whether mutation of SH3RF2 is causative for ASD and the mechanisms linking it to ASD traits. We find that mice with Sh3rf2 haploinsufficiency display significant deficits in social interaction and communication, as well as stereotyped or repetitive behaviors and hyperactivity and seizures. Disturbances in hippocampal dendritic spine development, aberrant composition of glutamatergic receptor subunits, and abnormal excitatory synaptic transmission were detected in heterozygous mutants. Remarkably, these defects are selectively unilateral. Our results support a notion that Sh3rf2 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis most likely resulting from deficits in synaptic function in the left hemisphere of the brain.