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An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This ‘synaptic autism pathway’ notably includes disruption of  SYN1  that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins ( SYN1-3 ) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in  SYN2  are associated with ASD in humans. The phenotype is apparent in males. Female carriers of  SYN2  mutations are unaffected, suggesting that  SYN2  is another example of autosomal sex-limited expression in ASD. When expressed in  SYN2   knockout neurons, wild-type human Syn II fully rescues the  SYN2  knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the  SYN2  knockout phenotype. These results identify for the first time  SYN2   as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD.

SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth