Submission Details

SYNJ1 was first reported in relation to autosomal recessive Developmental Epileptic Encephalopathy (DEE) in 2015 (Dyment et al. 2015 PMID: 25316601). Besides DEE, SYNJ1 has been associated with autosomal recessive Parkinson disease, early onset. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in phenotypes of these diseases. Therefore, the following disease entities have been split into two disease entities, Developmental and epileptic encephalopathy (OMIM:617389) and Parkinson disease, early onset (OMIM:615530). The split curation for autosomal recessive Parkinson disease, early onset may be curated by Parkinson disease GCEP. Eight SYNJ1 variants that have been reported in seven probands in five publications have been included in this curation. Typical phenotypes of these probands were neonatal onset seizures, hypotonia, severe to profound global developmental delay, and quadriplegia. Of the seven reported families, five had biallelic loss-of-function variants, and the default point of 1.5 was awarded for each allele, resulting in 15 points. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be LOF. This gene-disease association is also supported by an animal model (PMID: 10535736). The SYNJ1 knockout mice with seizures, failure to thrive, and ataxia, which manifest immediately after birth was given 2 points. In summary, SYNJ1 is definitively associated with autosomal recessive DEE. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.