STXBP1-E is caused by de novo heterozygous missense, frameshift, splice site and nonsense mutations in the STXBP1 gene. These mutations occur across all the different domains of the gene (see https://stxbp1.cncr.nl/stxbp1_disorders). Some mutations are known to be recurrent. In addition, intragenic deletions and larger whole-gene deletions have also been described. There is no established correlation between severity of seizures or developmental delay and the type and site of mutation.
The STXBP1 gene is located on chromosome 9q34.1 and encodes the syntaxin-binding protein 1, also known as MUNC18-1. This protein is predominantly expressed in the brain. Recent findings demonstrate that mutations in the STXBP1 gene lead to decreased cellular level of the Munc18-1 protein due to protein instability (Kovačević et al., 2018). This suggests haploinsufficiency as the underlying cause of disease. Decreased Munc18-1 level in the cell causes early synaptic fatigue that is more pronounced in GABA-ergic than in glutamatergic neurons (Toonen et al., 2006) leading to excitation-inhibition imbalance in brain that could underlie epilepsy in patients affected with STXBP1-E.
Most patients are diagnosed though next-generation sequencing methods such as gene panels or whole-exome sequencing. In some patients, a contiguous gene deletion involving the STXBP1 gene is discovered through microarray analysis.