SYT1

Molecular characteristics

To date, all confirmed pathogenic SYT1 mutations have been de novo heterozygous missense variants, clustered in the C2B domain of the protein. There are several recurrent variants within this region (I368T, D366E, N371K), and there is functional evidence for a dominant negative mechanism of these variants. It is currently unclear whether truncating variants, copy number variants, or variants outside of the C2B protein domain are pathogenic. Genotype-phenotype correlations are currently being characterized in view of marked variation in the severity of intellectual disability and movement disorder.

Diagnostic testing is via exome sequencing or whole genome sequencing, and either unbiased trio analysis or analysis of a relevant gene panel including SYT1.

SYT1 is a critical presynaptic mediator of neurotransmission, required for the activity-dependent fusion of vesicles with the neuronal membrane. Functional studies show that pathogenic variants slow the rate of stimulated vesicle release, and this is likely to be the main mechanism underlying the disorder. However the links from this cellular mechanism to complex neurodevelopmental symptoms are not yet fully understood. Clinical features share similarities with other disorders of vesicle fusion and disorders arising from other aspects of synaptic vesicle cycling.