Triplication of interferon receptor genes contributes to multiple hallmarks of Down syndrome

Trisomy of chromosome 21 causes Down syndrome, a condition characterized by developmental delays, cognitive impairments, immune dysregulation, and abnormal morphogenesis. Although four interferon receptors are encoded on chromosome 21 and interferon signaling is consistently activated by trisomy 21, the contribution of interferon hyperactivity to Down syndrome phenotypes remains undefined. We used genome-editing technology to reduce interferon receptor gene dosage in a mouse model of Down syndrome carrying triplication of ~120 protein-coding genes. Normalization of interferon receptor copy number rescued lethal anti-viral responses, decreased incidence of congenital heart defects, attenuated developmental delays, ameliorated craniofacial anomalies, and improved cognition. Therefore, triplication of interferon receptor genes contributes to multiple hallmarks of Down syndrome, supporting the notion that trisomy 21 elicits a form of interferonopathy amenable to therapeutic intervention.