Research team
STXBP1-related disorder: from genetic modifiers to clinical trial readiness.
Abstract
Background: STXBP1-related disorder (STXBP1-RD) is a severe monogenic neurodevelopmental disorder marked by substantial phenotypic variability that cannot be fully explained by the causal STXBP1 variant alone. Prospective longitudinal data are limited, the contribution of genetic background remains largely unexplored, and clinical trials for disease-modifying therapies are rapidly emerging. Objectives: This project aims to delineate the natural progression of STXBP1-RD, with a specific focus on seizures and motor functioning, to identify genetic modifiers underlying phenotypic variability, and to advance clinical trial readiness for future disease-modifying therapies. Methods: This project is embedded within the European STXBP1 Consortium (ESCO). I will analyze longitudinal data from the prospective ESCO natural history study to characterize seizure and motor trajectories and construct a multidomain severity scale capturing domain-specific disease burden. Whole genome sequencing will be used to assess polygenic influences and rare variants as modifiers of disease severity. Clinical and genomic data will be integrated using machine learning to define clinically meaningful subgroups to inform patient stratification in clinical trials. Expected outcomes: This integrative approach will enable genotype-phenotype correlations, improve prognostication, identify robust outcome measures, and establish a framework for stratified future clinical trials in STXBP1-RD.Researcher(s)
- Promoter: Weckhuysen Sarah
- Fellow: Swinnen Merel
Research team(s)
Funding
- FWO
- FWO
Project type(s)
- Research Project
STXBP1-related disorder: A prospective natural history study and search for genetic modifiers to enhance prognostication and uncover novel therapeutic targets.
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.Researcher(s)
- Promoter: Weckhuysen Sarah
- Fellow: Swinnen Merel
Research team(s)
Funding
- PRIVE - non profit
Project type(s)
- Research Project