Submission Details

SYN1 was first reported in relation to X-linked complex neurodevelopmental disorder in 2004 (Garcia et al., PMID: 14985377). To date, more than 40 SYN1 variants, mostly truncating, have been reported in individuals with variable neurodevelopmental phenotypes, including behavioral disturbances such as autism spectrum disorder or attention deficit-hyperactivity disorder (91%), epilepsy (82%), intellectual disability (77%), and developmental delay (70%) (PMID: 36568968). Reflex epilepsy, including bathing epilepsy, is characteristic of SYN1-related disorder. SYN1 variants co-segregating with disease have been reported in several large families (PMIDs: 14985377, 21441247, 28973667, 36568968). SYN1 variants predominantly affect males, while females exhibit a wider clinical heterogeneity and incomplete penetrance.

This gene-disease relationship is also supported by experimental evidence. SYN1 encodes synapsin 1, a presynaptic phosphoprotein involved in synaptic development, function, and plasticity. Syn1 knock-out mice exhibit enhanced stimulation-evoked epileptic seizures and autism-related behavioral abnormalities (PMIDs: 7568107, 7568108, 23280234). Overexpression of SYN1 nonsense variants in hippocampal neurons from Syn1 knock-out mice result in impaired axon elongation, disrupted synaptic vesicle pools, and formation of perinuclear aggregates (PMIDs: 21441247, 23818987).

In summary, there is definitive evidence supporting the relationship between SYN1 and X-linked complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 5, 2023 (SOP Version 9). This gene-disease relationship was originally evaluated on December 5, 2018 and given a Moderate classification. Curation of additional genetic evidence resulted in the classification being updated.