Boßelmann, Christian M.

Abstract Epilepsy affects more than 50 million individuals globally and has a substantial genetic component that remains to be completely understood. Traditional studies have focused on severe, early onset cases enrolled through clinical or research settings. Recent biobank‐based approaches, leveraging large‐scale population datasets, offer opportunities to explore genetic associations in broader epilepsy phenotypes, including milder, later onset forms. We analyzed data from more than 750 000 individuals across the UK Biobank, All of Us, and Massachusetts General Brigham Biobank, including 20 026 individuals with epilepsy. Rare coding variant burden testing revealed a significant association with LGI1 , a known epilepsy gene. Among the other top 10 associated genes, seven had prior evidence linking them to epilepsy ( GABRG2 , ATP1A3 ), neurological disorders with comorbid seizures ( HTRA2 , KRIT1 , STAG1 ), possible involvement in seizure phenotypes ( ADAM23 ), or roles in neuronal function ( PDCD4 ). Thus, we provide the first statistical evidence for ADAM23 as a candidate gene for epilepsy, based on the suggestive association signal combined with prior biological evidence from both animal (canine and murine) and one recent human epilepsy case study, potentially contributing to human epilepsy through its direct interaction with LGI1 . Phenome‐wide analyses highlighted the pleiotropic effects of epilepsy genes, with LGI1 and ADAM23 predominantly associated with epilepsy, whereas other genes such as KRIT1 , TSC1 , and TSC2 exhibited broader systemic involvement. Our study shows the potential of population‐scale genomic data and suggests that integrating these datasets with deep phenotyping will uncover more novel insights into epilepsy genetics in the future.

Abstract Background Genetic testing is increasingly used in presurgical evaluation, but the yield of resection across germline genetic epilepsies remains uncertain. Methods We conducted a systematic review of MEDLINE (PubMed) and Scopus and added cases from three institutional cohorts and the Pediatric Epilepsy Research Consortium (PERC) databases, including individuals with pathogenic/likely pathogenic germline variants besides tuberous sclerosis and neurofibromatosis who underwent resection or laser ablation. Etiologies were grouped into biologically informed categories (GATORopathies, vascular, overgrowth, CNVs, channelopathies, synaptopathies, other). Primary outcome was seizure freedom (Engel I) at last follow-up. Group comparisons used Fisher’s exact and Kruskal–Wallis tests (α=0.05; Bonferroni when applicable). Prespecified sensitivity analyses stratified by lesional status, excluded GATORopathies, and restricted to literature-only cases. Results We included 223 literature cases (64 studies), 35 institutional cases, and 11 PERC cases (n=269). Median follow-up was 24 months (IQR 12–48.0). Seizure freedom was achieved in: vascular disorders 14/19 (73.6%), GATORopathies 79/120 (67.5%), CNVs 18/31 (66.7%), overgrowth 7/13 (53.8%), other 16/25 (41.7%), channelopathies 13/43 (33.3%), and synaptopathies 4/18 (22.2%) (overall p<0.001). Among cases with known imaging, 208/253 (82.2%) had epileptogenic MRI lesions, including 64% of channelopathies and 80% of the synaptopathies. In univariate contrasts (each category vs all others), odds of seizure freedom were higher for vascular disorders (2.66-fold, 95% CI 0.87–9.72) and GATORopathies (2.46-fold, 95% CI 1.46–4.18), and lower for synaptopathies (∼4.2-fold lower, OR 0.24, 95% CI 0.05– 0.78) and channelopathies (∼4.5-fold lower, OR 0.22, 95% CI 0.09–0.48). Direction and magnitude were consistent across prespecified sensitivity analyses (lesional-only, literature-only, exclusion of GATORopathies). Conclusions Resective surgeries can be effective in germline genetic epilepsies, but outcomes vary by pathway. Disorders with discrete, lesional substrates (GATORopathies, vascular) show the highest likelihood of seizure freedom, whereas channelopathies and synaptopathies, despite the presence of MRI lesions, have substantially lower yields even in lesional cases. Prospective, genotype-aware surgical registries with standardized reporting (EEG, imaging, pathology) and time-to-event outcomes are needed to refine the selection of surgical candidates and quantify seizure and non-seizure-related outcomes.

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 Rationale Neurodevelopmental disorders (NDDs) are characterised by significant challenges in communication, social interaction, and adaptive function, often impacting quality of life. Previous studies support genetic influences on the communication abilities of individuals with NDD, but were either limited to single genetic conditions or to small cohorts with a limited selection of communication measures. Methods We analysed caregiver-reported communication abilities in 79,518 individuals with NDD from the Simons Searchlight and SPARK registries: 4,439 with a CNV-based or monogenic NDD and 75,079 with autism spectrum disorder (ASD) without a known genetic cause (idiopathic ASD) as controls. For analysis, we a priori selected 10 communication-related measures based on their availability in the study cohorts, coverage of distinct communication aspects, and their frequent use in neurodevelopmental phenotyping, yielding 177,328 data points across all study cohorts. The individuals in the Searchlight registry were divided into a Discovery cohort (the 15 most prevalent genetic NDD conditions) and a Confirmation cohort (all other genetic NDD conditions). A second Confirmation cohort was generated using all individuals with genetic ASD forms from the SPARK registry. We then tested each of the three case cohorts and each genetic condition represented in the Discovery cohort against the ASD control cohort. Developmental trajectories were assessed through testing of participants grouped by age at evaluation. Results Measure-level analyses demonstrated significant associations between genetic status and communication abilities, differences in communication abilities between classes of genetic variants (monogenic vs. CNV-based NDDs), and variability between specific genetic NDD conditions. CNV-based NDDs showed milder communication impairment, outperforming idiopathic ASD controls in 9/10 communication measures, whereas monogenic NDD conditions had more pervasive impairments, especially in verbal communication. Although impaired in verbal communication, five monogenic NDD conditions showed at least suggestive strengths in nonverbal and social communication relative to idiopathic ASD controls ( CSNK2A1 , CTNNB1 , SETBP1 , MED13L , and PPP2R5D ), specifically in using gestures. Developmental trajectory analyses revealed STXBP1 as the gene group at highest risk of developmental stagnation in communication abilities. Conclusions These findings underscore the potential of precision speech-language pathology (SLP) approaches tailored to the specific verbal and nonverbal communication strengths and weaknesses of genetic groups. We also provide evidence for measurable improvements and declines in communication abilities with age at the group level, highlighting the need for developmentally informed care. By integrating genetic insights into clinical practice, precision SLP approaches may enhance communication outcomes and developmental progress and improve quality of life for individuals with genetic NDDs.

4-Aminopyridine is a potential therapeutic option for a subgroup of patients with KCNA2 -encephalopathy and gain-of-function variants.