SYT2 was first reported in relation to autosomal dominant presynaptic congenital myasthenic syndrome 7A and distal motor neuropathy (CMS7A) in 2014 (Hermann et al., PMID: 25192047). Patients present with early onset foot deformities and distal muscle weakness. Electrophysiologic studies show abnormal synaptic transmission at the neuromuscular junction (NMJ) and low amplitude compound muscle action potentials. SYT2 has also been associated with autosomal recessive presynaptic congenital myasthenic syndrome 7B (CMS7B). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into autosomal dominant CMS7A (OMIM: 616040) and autosomal recessive CMS7A (OMIM: 619461).
Six variants (missense and in-frame deletion) reported in six probands in five publications were included in this curation, reaching a total of five points for genetic evidence (PMID: 30533528, PMID: 25192047, PMID: 33105646, PMID: 33320396, PMID: 34037996). SYT2 encodes for Synaptotagmin 2, a calcium sensor protein involved in synaptic vesicle exocytosis at the NMJ. Variants cluster in the C2B calcium binding domain and are upgraded if located in a hotspot region. Variants were also upgraded for presenting with very consistent phenotypes.
Evidence supporting this gene-disease relationship includes experimental data from two model systems: a transgenic drosophila model and a knockout mouse model. DSYT1 in drosophila is a single homolog for SYT1, SYT2, and SYT9 in humans. DSYT1 null drosophila exhibit abnormal synaptic transmission at the NMJ (PMID: 25192047). Transgenes of WT and the mutation homologous to the human Asp307Ala variant were expressed in DSYT1 null drosophila. Staining revealed co-localization of WT and mutant Synaptotagmins. Expression of WT Synaptotagmin showed phenotypic rescue in DSYT1 null drosophila, while expression of mutant Synaptotagmin failed to rescue the phenotype. Expression of mutant synaptotagmin in the presence of endogenous DSYT1 provided evidence of a dominant negative effect. This model was also used to study the Ile371Lys variant and produced similar findings for co-localization, failure of phenotypic rescue with expression of mutant synaptotagmin, and a dominant negative effect with expression of mutant Synaptotagmin in the presence of endogenous DSYT1 (PMID: 30533528). A SYT2 knockout mouse model was generated in 2006 (PMID: 17192432). The knockout was lethal and mice developed abnormal synaptic transmission at the neuromuscular junction. No rescue experiments were attempted. The drosophila model received 1.5 points and the mouse model received 1 point as experimental evidence. Both were downgraded for not representing an autosomal dominant mode of inheritance as a knockout model.
In summary, there is moderate evidence to support this autosomal dominant gene-disease relationship. No contradictory evidence has emerged.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.