Abstract
STXBP1-related disorder (STXBP1-RD) is a rare neurodevelopmental disorder caused by pathogenic variants in the STXBP1 gene, a key regulator of synaptic transmission. The disorder is characterized by early-onset epilepsy, global developmental delay, movement disorders, and behavioral challenges, with wide phenotypic variability and no clear genotype–phenotype correlation. Currently, there are no disease-modifying treatments, and available therapies primarily target seizures, leaving significant unmet needs in developmental, motor, and behavioral domains.
In preparation for upcoming clinical trials, the European STXBP1 Consortium (ESCO) has established a multicenter European registry and prospective natural history study to characterize the longitudinal course of STXBP1-RD and identify relevant clinical endpoints and outcome measures. This PhD project will focus on conducting and analyzing data from this natural history study to deepen understanding of disease progression and variability.
A second key objective is to identify genetic modifiers that may explain interindividual differences in disease severity. Using whole-genome sequencing of 130–150 individuals with STXBP1-RD—extended through international collaborations to a cohort of approximately 300 participants—the project will investigate common and rare variants that influence disease expression. Analyses will include polygenic risk scores for epilepsy and cognition, exploration of regulatory variants in STXBP1, and burden testing in relevant gene sets.
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