Meskis, Mary Anne

Abstract Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

Abstract Objective This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently approved, DS‐specific therapies and emerging disease‐modifying treatments. Methods A core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease‐modifying therapies) and nominated the 31‐member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS. Results There was strong consensus that infants 2–15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first‐ to third‐line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease‐modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians. Significance This International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease‐modifying therapies.

AbstractObjectiveVaccination against the SARS‐CoV‐2 virus is a primary tool to combat the COVID‐19 pandemic. However, vaccination is a common seizure trigger in individuals with Dravet syndrome (DS). Information surrounding COVID‐19 vaccine side effects in patients with DS would aid caregivers and providers in decisions for and management of COVID‐19 vaccination.MethodsA survey was emailed to the Dravet Syndrome Foundation's Family Network and posted to the Dravet Parent & Caregiver Support Group on Facebook between May and August 2021. Deidentified information obtained included demographics and vaccination status for individuals with DS. Vaccine type, side effects, preventative measures, and changes in seizure activity following COVID‐19 vaccination were recorded. For unvaccinated individuals, caregivers were asked about intent to vaccinate and reasons for their decision.ResultsOf 278 survey responses, 120 represented vaccinated individuals with DS (median age = 19.5 years), with 50% reporting no side effects from COVID‐19 vaccination. Increased seizures following COVID‐19 vaccination were reported in 16 individuals, but none had status epilepticus. Of the 158 individuals who had not received a COVID‐19 vaccination, 37 were older than 12 years (i.e., eligible at time of study), and only six of these caregivers indicated intent to seek vaccination. The remaining 121 responses were caregivers to children younger than 12 years, 60 of whom indicated they would not seek COVID‐19 vaccination when their child with DS became eligible. Reasons for vaccine hesitancy were fear of increased seizure activity and concerns about vaccine safety.SignificanceThese results indicate COVID‐19 vaccination is well tolerated by individuals with DS. One main reason for vaccine hesitancy was fear of increased seizure activity, which occurred in only 13% of vaccinated individuals, and none had status epilepticus. This study provides critical and reassuring insights for caregivers and health care providers making decisions about the safety of COVID‐19 vaccinations for individuals with DS.