Summary Background Missense variants in genes encoding GABAA receptors are involved in the pathophysiology of common and rare epilepsies. Variant effects on channel biophysical function are associated with key clinical characteristics and treatment response. Predicting variant effects is therefore key to improving care for individuals with GABAA receptor-related disorders. Methods We collected data from 505 affected individuals with 272 (likely) pathogenic GABAA receptor missense variants (GABRA1, GABRB2, GABRB3, GABRG2). All variants were evaluated with in-vitro electrophysiology. Variants were annotated with features based on sequence, structure, and phenotype. Model performance was estimated using cross-validation and external validation on a further 197 individuals with 138 (likely) pathogenic variants. Findings Our models enable highly accurate prediction of missense variant effects in GABAA (AU-ROC 0.862–0.946), outperforming state-of-the-art models (AU-ROC 0.495–0.756) and clinical decision-making. Model scores correlated with GABA sensitivity and were consistent with expert-based structure–function hypotheses, supporting plausibility. Predictions on population variants were similar to functionally neutral variants, while cases from ClinVar were similar to GOF/LOF variants. Our model may provide additional evidence for 5–25% of variants in ClinVar. Lastly, we show that we can predict likely clinical characteristics from variant information alone (median Lin similarity 0.754 IQR 0.161). Interpretation We demonstrate accurate missense variant effect prediction in GABAA receptors with rigorous validation across a large dataset of functionally tested variants. These predictions may facilitate timely diagnosis and precision treatment of individuals with GABAA receptor-related disorders, pending prospective clinical validation. A web interface, precomputed scores, and calibrated score thresholds for all possible variants are openly available. Funding Else Kröner-Fresenius-Stiftung; German Federal Ministry of Research, Technology and Space; German Research Foundation; Medical Faculty University of Tübingen; Lundbeck Foundation; Novo Nordisk Foundation.
C. Boßelmann, S. Ortiz, R. Dahl et al.· EBioMedicine· 0 citations
BACKGROUND
Variants in STX1B/syntaxin-1B are linked to a spectrum of fever-associated epilepsy syndromes. While studies in murine models have provided mechanistic insights, their relevance to human disease in a heterozygous context may be limited.
METHODS
We investigated two pathogenic STX1B variants using isolated single neurons and neuronal network cultures derived from patient-specific induced pluripotent stem cells. These carried either a de novo p.G226R variant, associated with severe developmental epilepsy, or an InDel variant (p.K45delinsRCMIE/p.L46M) linked to a transient familial seizure syndrome. Synaptic function and network excitability were assessed using patch-clamp and multi-electrode array recordings, alongside morphological and transcriptomic profiling.
FINDINGS
G226R exhibited both gain- and loss-of-function characteristics, with increased miniature excitatory postsynaptic current frequency in networks but not in autapses, and synaptic failure during sustained high-frequency stimulation. For the InDel variant, the predicted loss-of-function phenotype based on reduced syntaxin-1B levels was not detectable at the single-cell level, likely masked by compensatory synaptic upregulation. At the network level, however, both variants were associated with neuronal hyperexcitability, characterised by more frequent and prolonged bursting activity, with a much stronger phenotype in G226R-containing networks. Transcriptomic profiling revealed a differential dysregulation of synaptic and other neuronal genes.
INTERPRETATION
The divergence between morphological, electrophysiological and transcriptomic findings suggests that compensatory mechanisms may contribute to network hyperexcitability. Initially engaged to maintain homoeostasis, they may ultimately contribute to a pathological network state. The graded severity of network alterations across STX1B variants correlates with the clinical phenotypes.
FUNDING
BMBF (Treat ION-01GM2210A, SNAREopathies-01EW1809A), 2023 FEBS Summer Fellowship, Fortüne programme (2610-0-0), EKFS college precise.net, Open Access Publishing Fund of University of Tübingen.
Carolin Haag, Felix Gsell, Oleg Vinogradov et al.· EBioMedicine· 0 citations
OBJECTIVE
The polygenic risk score (PRS) for individuals with genetic generalized epilepsy (GGE) quantifies the common risk variants in genes identified in genome-wide association studies. We hypothesized that the phenotype of GGE patients differs based on their GGE PRS.
METHODS
We identified participants with highest (n = 59) versus lowest (n = 48) PRS from the GGE patients (n = 2256) recruited through the Epi25 Collaborative for comparison. Detailed clinical data were acquired retrospectively for the 59 high PRS and 48 low PRS individuals with GGE from the Epi25 database and from the contributing centers. For validation, we accessed a larger cohort (n = 1175) of patients with GGE included in the Epi25 Collaborative.
RESULTS
This study found no difference in phenotypic features of patients between the high-PRS GGE and low-PRS GGE subgroups, including age at onset, family history, and specific GGE syndrome. However, more patients from the lowest compared to the highest PRS subgroup were pharmacoresistant (31.7% vs. 8.9%, p = .01). On validation in a larger cohort, the PRS did not differ in the group of pharmacoresistant compared to nonpharmacoresistant patients.
SIGNIFICANCE
No meaningful association between PRS and age at onset, history of febrile seizures, pre-/perinatal complications, epilepsy syndromes, seizure types, co-occurrence of functional/dissociative (nonepileptic) seizures, psychiatric comorbidities, electroencephalographic/magnetic resonance imaging findings, or drug response could be demonstrated in this study of people with GGE.
Sophie von Brauchitsch, Nils Hartung, R. Karge et al.· Epilepsia· 0 citations
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