Abstracts

Rationale: Syntaxin-binding protein 1 (STXBP1) mutations have been reported across a spectrum of neurodevelopmental disorders, including Otahara syndrome and other epileptic encephalopathies. In order to delineate the phenotypic complexity of cases, it is necessary to analyze the STXBP1 mutation with consideration for the sequence context. Here, we report the first case of a successfully treated epilepsy surgery patient with a heterozygous STXBP1 germline mutation that was mosaic within a surgically resected area populated with dysplastic cells.Methods: Patients undergoing resective epilepsy surgery for refractory focal epilepsy that was associated with suspected cortical dysplasia were recruited prospectively for genetic study. For the current patient, a targeted (70 genes) sequencing approach was applied to identify rare pathogenic mutations. DNA from peripheral blood was collected from the nuclear family. DNA was also collected from resected left lateral temporal cortex tissue with dysplastic neurons. We applied droplet digital PCR (ddPCR) technology to validate the copy number variation (CNVs).Results: We have identified a de novo 4.9Kb deletion impacting exon 3-4 of the STXBP1 gene in a 6-year old proband (male) diagnosed with refractory focal-onset epilepsy with initial infantile spasms, global developmental disorder, autism spectrum disorder and MRI imaging suspicious for focal cortical dysplasia type 1 in the left anterior temporal cortex. The patient underwent left anterior temporal lesionectomy including mesial structures. Surgical pathology demonstrated nodular heterotopias in the superior temporal gyrus and deep temporal white matter with collections of cells with small round nuclei and clear cytoplasm. Hippocampus, para-hippocampal gyrus and lateral temporal cortex were normal. The ddPCR result revealed heterozygous state of the deletion in blood, whereas, evidence of the mosaic presence of heterozygous and homozygous deletions was observed within the dysplastic tissue cell population of the proband. The patient has been seizure free since surgery.Conclusions: We report a novel de novo mutation within STXBP1 in a patient with a complex neurodevelopmental phenotype and focal epilepsy with areas of dysplastic neurons. This is the first case of STXBP1 showing formation of mosaic copy number variations within dysplastic brain cells. These findings suggest a role for STXBP1 in malformations of cortical development and a role for epilepsy surgery in the management of STXBP1-associated epilepsy.