SHANK3

SHANK3 encodes a multidomain scaffold protein that connects neurotransmitter receptors, ion channels, and membrane proteins to the actin cytoskeleton in postsynaptic densities and regulates synapse formation and dendritic spine maturation. Loss-of-function mutations cause autosomal dominant Phelan-McDermid syndrome (22q13.3 deletion syndrome) characterized by autism spectrum disorder, intellectual disability, and neurological symptoms, as well as schizophrenia type 15. The protein is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the primary disease mechanism.