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Objective STXBP1‐related disorders are rare genetic epilepsies and neurodevelopmental disorders, but the impact of symptoms across clinical domains is poorly understood. Disease concept models are formal frameworks to assess the lived experience of individuals and their families and provide a basis for generating outcome measures. Methods We conducted semistructured, qualitative interviews with 19 caregivers of 16 individuals with STXBP1‐related disorders and 7 healthcare professionals. We systematically coded themes using NVivo software and grouped concepts into the domains of symptoms, symptom impact, and caregiver impact. We quantified the frequency of concepts throughout the lifespan and across clinical subgroups stratified by seizure history and developmental trajectories. Results Over 25 hours of interviews, we coded a total of 3626 references to 38 distinct concepts. In addition to well‐recognized clinical features such as developmental delay (n = 240 references), behavior (n = 201), and seizures (n = 147), we identified previously underrepresented symptoms including gastrointestinal (n = 68) and respiratory symptoms (n = 24) and pain (n = 30). The most frequently referenced symptom impacts were autonomy (n = 96), socialization (n = 64), and schooling (n = 61). Emotional impact (n = 354), support (n = 200), and daily life & activities (n = 108) were highly cited caregiver impacts. We found that seizures were more commonly referenced in infancy than in other age groups, while behavior and socialization were more likely to be referred to in childhood. We found that caregivers of individuals with ongoing seizures were less likely to reference developmental delay, possibly due to the relatively high impact of seizures. Significance STXBP1‐related disorders are complex conditions affecting a wide range of clinical and social domains. We comprehensively mapped symptoms and their impact on families to generate a comprehensive disease model as a foundation for clinical endpoints in future trials.

Introduction Pathogenic variants in STXBP1 cause a spectrum of disorders mainly consisting of developmental and epileptic encephalopathy (DEE), often featuring drug-resistant epilepsy. An increased mortality risk occurs in individuals with drug-resistant epilepsy and DEE, with sudden unexpected death in epilepsy (SUDEP) often the major cause of death. This study aimed to identify the rate and causes of mortality in STXBP1 -related disorders. Methods Through an international call, we analyzed data on individuals with STXBP1 pathogenic variants, who passed away from causes related to their disease. Results We estimated a mortality rate of 3.2% (31/966), based on the STXBP1 Foundation and the STXBP1 Global Connect registry. In total, we analyzed data on 40 individuals (23 males) harboring pathogenic STXBP1 variants, collected from different centers worldwide. They died at a median age of 13 years (range: 11 months—46 years). The most common cause of death was SUDEP (36%), followed by pulmonary infections and respiratory complications (33%). The incidence of SUDEP peaked in mid-childhood, while non-SUDEP causes were more frequent in early childhood or adulthood (p = 0.006). In the most severe phenotypes, death was related to non-SUDEP causes ( p  = 0.018). Conclusion We found a mortality rate in STXBP1 -related disorders similar to other DEEs, with an early age at death and SUDEP as well as pulmonary infections as the main cause of death. These findings assist in prognostic evaluation and genetic counseling for the families. They help to define the mortality risk of STXBP1 -related disorders and implement preventative strategies.

IntroductionIn the last 60 years, newborn bloodspot screening (NBS) has expanded as a public health intervention from a single severe childhood genetic disease (SCGD) to up to as many as 80 SCGD and testing of ~40 million newborns/year worldwide. However, the gap between current NBS and its potential to increase the efficiency, effectiveness and global equity of healthcare delivery for SCGD is large and rapidly growing. There are now effective therapeutic interventions—drugs, diets, devices and surgeries—for up to 2000 SCGD. Since almost all SCGD can be identified by bloodspot genome sequencing, it has been a longstanding goal to supplement current NBS with genome sequencing-based NBS (gNBS) for all eligible SCGD. We recently described a novel gNBS platform (named Begin Newborn Genome Sequencing (BeginNGS)) with the potential to overcome several major challenges to gNBS (cost, scalability, false positives and an unprepared healthcare workforce). A pilot clinical trial of BeginNGS for 412 SCGD in a level IV neonatal intensive care unit (NICU) had a true positive rate of 4.2%, sensitivity of 83%, positive predictive value of 100% and clinical utility rate of 4.2%, indicating readiness of the platform for use in a powered, multicentre study.Methods and analysisThe BeginNGS study is a single group, international, multicentre, adaptive clinical trial to compare utility, acceptability, feasibility and cost-effectiveness of BeginNGS gNBS (experimental intervention) with standard NBS (control). A minimum of 10 000 neonates (aged <28 days, maximum of 100 000) will be enrolled across 25 racial, ethnic and ancestry populations and five enrolment site types (high-risk obstetrician offices, labour induction office visits, newborn nurseries, NICUs and well-baby visits). BeginNGS is gNBS for circa 2000 SCGD (currently 508 SCGD). The primary objective of the trial is to generate equitable evidence to support broad implementation of gNBS. Enrolled newborns receive both interventions (BeginNGS and standard of care NBS). Newborns who screen positive receive confirmatory testing and medical follow-up for at least 1 year to obtain outcomes data. The primary outcome measure is clinical utility, defined as the proportion of diagnoses identified by BeginNGS and state NBS during infancy that are likely to benefit (likely to have an improved outcome) from treatment. We hypothesise that BeginNGS has a greater rate of clinical utility than standard NBS. An adaptive design was chosen rather than a traditional, fixed design to allow accumulating results to make the trial more efficient, informative, equitable and ethical by addition or removal of SCGD and genetic variants, population enrichment (for under-represented racial, ethnic and ancestral groups) and sample size re-estimation. Adaptive design will also facilitate meta-analysis with other clinical trials of gNBS, providing greater power to test utility in ultra-rare SCGD. Parents will be approached (in person, via phone or via electronic communication) to provide informed consent to enrol their newborns prenatally, postnatally in newborn nurseries or NICUs or at well baby outpatient visits. This study is part of phase III of the BeginNGS programme. Patient and public voices have been engaged in the design and execution of each BeginNGS phase through individuals and groups joining the BeginNGS consortium and participating in the family and community engagement work group. gNBS has the potential to transform the way we diagnose and treat childhood genetic diseases. Preliminary data suggest that national adoption of BeginNGS for all births has the potential to improve outcomes of >50 000 US children per year.Ethics and disseminationThis study was approved by the WCG Clinical institutional review board on 14 February 2024, and the most recent amendment approved on 7 October 2025 (approval number 20235517). Study findings will be shared through research consortium workshops, national and international conferences, community presentations and peer-reviewed journals.Trial registration numberNCT06306521.