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.

Super-refractory status epilepticus (SRSE) is a life-threatening neurological emergency with limited treatment options. A ketogenic diet (KD) is increasingly considered as a rescue therapy, but controlled data in critically ill adults remain scarce. This study aimed to evaluate the feasibility, safety, and clinical effects of KD in adult SRSE using a severity-matched control group. A retrospective, severity-matched cohort study compared adult patients with SRSE treated with KD to matched controls. The primary outcome was SRSE resolution. Secondary outcomes included the modified Rankin Scale (mRS) and mortality at 3 and 6 months. Time-dependent and multivariate Cox regression models adjusted for illness severity (including age and Status Epilepticus Severity Score [STESS]) and delayed KD initiation. Despite pragmatic matching, baseline differences in age, STESS, and seizure type were addressed through multivariate adjustment. A total of 34 adult patients with SRSE were analyzed (18 KD, 16 control). KD was initiated after a mean of 16.6 ± 9.4 days and maintained for 12.9 ± 7.7 days. Ketosis was achieved in 33

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.

Abstract Gain-of-function variants (GOF) in SCN8A , which encodes the Na V 1.6 sodium channel, lead to epilepsy syndromes ranging from drug-responsive self-limited (SeLIE) and intermediate epilepsy to drug-resistant developmental and epileptic encephalopathy (DEE). It is currently unclear why individuals with SCN8A GOF variants show variable responses to sodium channel blockers (SCBs). Here, we compared the clinical characteristics of 173 individuals with 25 different SCN8A GOF variants following the hypothesis that carriers of variants affecting activation gating respond less well to SCBs than those with variants affecting fast inactivation gating, given that use-dependent SCBs preferentially target inactivated channel states. We found that individuals with variants altering channel activation gating were more severely affected than those with variants altering inactivation properties: They had an earlier age at onset (3 vs. 5 months, P < 0.0001), higher prevalence of DEE (75% vs. 39%; P < 0.0001), and poorer response to SCBs (20% vs. 69% seizure free; P < 0.0001). We performed pharmacological studies on representative and recurrent variants from each group: two variants (F846S and M1760I) causing hyperpolarizing shifts of the voltage-dependent activation curves, and two variants (G1475R and N1877S) causing depolarizing shifts of the voltage-dependent fast inactivation curves. Phenytoin failed to suppress neuronal firing in neurons expressing activation-related variants, but showed good suppressing effects in neurons expressing inactivation-related variants. In contrast, PRAX-330, a new SCB, which showed much faster binding rates than phenytoin, was effective for both groups of variants by markedly reducing neuronal firing through rapidly and persistently stabilizing Na V 1.6 in the inactivated state. Our findings provide new insights into the mechanism of drug-resistance in SCN8A -DEE and support PRAX-330 and compounds with similar pharmacological properties as a promising preclinical candidate for targeted therapies.

OBJECTIVE:The detection of subtle epileptogenic lesions such as focal cortical dysplasias (FCDs) is a clinical challenge in the management of drug-resistant focal epilepsy (DRFE). Ultra-high-field (UHF) magnetic resonance imaging (MRI) offers increased signal-to-noise ratios and spatial resolution compared to 3-T MRI and may improve diagnostic yield. METHODS:We recruited n = 21 DRFE patients (with 3-T MRI findings: two positive, three equivocal, 16 negative) undergoing presurgical workup and n = 20 healthy controls for 9.4-T MRI (.8 mm isotropic magnetization-prepared 2 rapid acquisition gradient echo [MP2RAGE], slabs of .375 × .375 × .8 mm T2*-weighted gradient echo) and 3-T MRI (magnetization prepared rapid acquisition gradient echo [MPRAGE], magnetization-prepared 2 rapid acquisition gradient echo [MP2RAGE], fluid-attenuated inversion recovery [FLAIR]) acquisitions. Visual review for possible epileptogenic lesions was performed by clinical experts. For histopathologically confirmed FCDs, we extracted surface-based quantitative features (cortical thickness, quantitative T1, FLAIR, T2*, and quantitative susceptibility mapping values) across cortical depths and distances from the lesion center and performed high-resolution cortical profiling of 9.4-T T2* values. RESULTS:In two patients with histopathologically confirmed FCD IIb, lesions were visible with distinct qualitative and quantitative features at both field strengths. One of these type IIb FCDs showed a focal cortical T2* reduction at 9.4 T that could be quantified via automated cortical profiling, consistent with the previously described "black line sign." No new epileptogenic lesions were identified at 9.4 T in 3-T MRI-negative patients, who also had no histological evidence of such lesions. SIGNIFICANCE:9.4-Tesla MRI findings in epileptogenic lesions underlying DRFE are consistent with those on 3-T MRI. UHF T2*-weighted sequences may be useful to detect the black line sign and thereby refine surgical or ablation targeting for some FCDs. Assessment of the diagnostic yield of 9.4-T MRI was limited by the lack of 3-T MRI-negative but histopathologically confirmed cases and by the unavailability of parallel transmit and FLAIR at 9.4 T. Further optimization of UHF protocols and analysis methods on larger cohorts may enhance clinically applicable diagnostic benefits.

IntroductionThe role of antineuronal antibody titres in the acute and long-term diagnostic and therapeutic management of autoimmune encephalitis (AE) remains unclear. In this retrospective monocentric cohort study, we aimed to (I) identify specific characteristics in antibody testing distinguishing AE from non-AE patients, (II) evaluate the prognostic significance of antineuronal antibody findings and (III) assess outcomes and long-term immunotherapy in patients with AE.MethodsPatients with suspected autoimmune-associated neuropsychiatric conditions underwent antineuronal antibody testing between 01/2017 and 03/2023. Patients with positive antibody tests were stratified into AE and non-AE groups based on the clinical criteria proposed by Graus and colleagues. Long-term outcomes, antibody titres, and therapeutic strategies were analysed in AE patients over a three-year follow-up period. Among 2,466 patients tested, 53 met the diagnostic criteria for AE.ResultsIn AE patients with paired serum and CSF samples (n = 44), antibodies were detectable in both serum and CSF in 55% of cases (n = 24), in serum only in 36% (n = 16), and in CSF only in 9% (n = 4). AE patients with poor outcomes (n=5) showed a trend toward higher median CSF titres in the acute phase and at four months post-onset compared to patients with good outcomes (n=14); however, differences were not statistically significant. Regarding long-term immunotherapy, rituximab-treated patients experienced fewer relapses than those receiving intravenous-immunoglobulins (IVIG; p-value = 0.02).DiscussionThese exploratory results from a small, heterogeneous cohort require confirmation in larger, prospective studies. Based on our data regarding serum and CSF antibodies, in a resource- limited setting we propose a stepwise diagnostic approach starting with serum screening; in suspected anti-NMDAR-AE, initial paired serum/CSF testing remains essential. If antibodies are detected in serum, additional CSF antibody testing may provide diagnostic confirmation and help guide treatment decisions, as high acute-phase CSF titres may suggest poorer long-term outcomes; however, this potential prognostic value requires confirmation in larger, antibody-specific studies.

1. Abstract Background The detection of subtle epileptogenic lesions such as focal cortical dysplasias (FCDs) is a clinical challenge in the management of drug-resistant focal epilepsy (DRFE). Ultra-high field (UHF) MRI offers increased signal-to-noise ratios and spatial resolution compared to 3 Tesla (T) MRI and may improve diagnostic yield. Here, we present a 9.4T MRI cohort study of patients with DRFE. Methods We recruited n=21 DRFE patients (with 3T-MRI findings: 2 positive, 3 equivocal, 16 negative) undergoing presurgical workup, and n=20 healthy controls for 9.4T MRI (0.8 mm isotropic MP2RAGE, slabs of 0.375 × 0.375 × 0.8 mm T2*-weighted GRE) and 3T MRI (MP2RAGE, FLAIR) acquisitions. Visual review for possible epileptogenic lesions was performed by clinical experts. For histopathologically confirmed FCD lesions, we extracted surface-based quantitative features (cortical thickness, qT1, FLAIR, T2*, and QSM values) across cortical depths and distances from the lesion centre and performed high-resolution cortical profiling of 9.4T T2* values. Results No new epileptogenic lesions were visually identified at 9.4T in 3T MRI negative patients. In the two patients with histopathologically confirmed lesions, the FCD IIb lesions were visible with distinct qualitative and quantitative features at both field strengths. One of these FCD IIb showed a focal cortical T2* reduction at 9.4T that could here be quantified via automated cortical profiling, consistent with the previously described “black line sign”. Conclusion 9.4T MRI findings in epileptogenic lesions underlying DRFE are consistent with those on 3T MRI. While additional lesions were not identified in patients with negative 3T MRI, higher resolution T2*-weighted sequences can reveal a feature not seen at 3T: Cortical profiling of FCDs highlights the black line sign and can possibly help refine surgical or ablation targeting for some FCDs. Further optimization of UHF protocols and analysis methods on larger cohorts may reveal clinically applicable diagnostic benefits. Key Points - 9.4T MRI shows focal cortical dysplasia (FCD) IIb with distinct qualitative and quantitative features that are consistent with 3T MRI. - High-resolution quantitative T2* maps at 9.4T may provide additional information for defining resection or ablation targets in FCDs. - Without using parallel transmit technology, artefacts in the temporal lobes pose a limitation of 9.4T MRI in presurgical epilepsy workup.

Idiopathic generalized epilepsy is characterized by marked brain network alterations as assessed using electrophysiology. Logistical challenges and the need for a volumetric MRI often hinder the clinical application of high-density EEG or magnetoencephalography. This study investigates the influence of EEG channel density and the head model on brain metrics derived from 256-channel EEG and 19-channel routine EEG in two samples balanced for age and sex. First, we evaluated resting-state data from 35 individuals with idiopathic generalized epilepsy and 54 healthy controls collected using the 256-channel setup. Data were analysed at full density and then iteratively downsampled to lower densities. Source reconstruction was performed either using individual MRI data or a standard brain template and dynamic imaging of coherent sources. We assessed EEG power and connectivity (imaginary part of coherency) group differences at all channel compositions, head model types and parcellations (cortical vertices, anatomical and network parcellations). Second, a routine sample recorded with 19 channels was analysed to validate findings in a real epilepsy monitoring scenario (71 patients, 43 controls). We found that lower-density arrays reliably identified global group differences for both power and connectivity and in frequency bands for which the strongest effects were observed. The spatial similarity of the results for the 256 channels set and those with fewer channels were good to moderate for power (r spin ∼0.97 to 0.33), but dropped for connectivity with fewer than 64 channels (r spin ∼0.78 to -0.12). Comparing individual and canonical head models revealed consistent effects (r spin ∼0.77 to 0.5), with coarser brain parcellations increasing stability for low-density maps. In sum, low-density EEG arrays suffice for detecting global alterations in idiopathic generalized epilepsy, particularly in signal power. Our findings advocate for leveraging clinical EEG for brain-wide analyses in idiopathic generalized epilepsy while emphasizing the need for high-density coverage if spatial precision is needed. Canonical head models are a viable alternative if no individual MRI is available, especially for regional- or network-level assessments.

INTRODUCTION:Despite licensing many new antiseizure drugs over the last few decades, the proportion of pharmacoresistant epileptic seizures has remained largely unchanged at about 30%. However, recent progress in genetics has revealed new and more specific therapeutic targets that can be addressed through improved drug design and advancements in gene therapy, such as improved antisense oligonucleotide chemistry. Furthermore, many of these developing new precision therapies hold the promise of shifting from purely symptomatic toward disease-modifying treatment, particularly in the field of developmental and epileptic encephalopathies. AREAS COVERED:This article focuses on novel potential therapeutic targets, including those encoded by causative genes for epileptic syndromes and those that show promise for favorably impacting common epilepsies or epileptogenesis. The covered areas are organized according to different molecular protein targets. EXPERT OPINION:Therapy in the near future will likely be based predominantly on specific small molecules or gene therapies, such as antisense oligonucleotides. Among currently used allele-specific therapeutic designs, only some loss- or gain-of-function pathological variants are expected to profit from them. Allele-specific gene therapy may be a promising treatment for those diseases that would not benefit from currently used allele-nonspecific designs.

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.

OBJECTIVE:Focal cortical dysplasia (FCD) causes drug-resistant epilepsy requiring presurgical evaluation. Invasive electroencephalographic (EEG) studies demonstrate that sleep modulates epileptic activity, including interictal epileptiform discharges (IEDs), fast oscillations (FOs) in the beta (14-40 Hz) and gamma (40-80 Hz) frequency bands, and seizures. This study aimed to quantify sleep-associated changes in IEDs, FOs, and seizures in FCD patients using noninvasive magnetoencephalography (MEG). METHODS:Nineteen patients with FCD were prospectively recruited and underwent simultaneous MEG/EEG recordings lasting 89 ± 19 min during daytime sleep. Sleep stages were classified from the EEG. Beamformer source signals were computed from the MEG signal to enhance sensitivity for visual detection of IEDs, FOs in the beta and gamma frequency bands, and seizures. Magnetic source imaging (MSI) was performed using the Maximum Entropy on the Mean (MEM) method, which is particularly sensitive to the spatial extent of sources, enabling accurate localization of epileptic activity. RESULTS:N1 sleep was reached in 17 of 19 patients and N2 sleep in 14 of 19 patients. Compared to wakefulness, sleep recordings showed significantly higher rates of FOs and seizures (both p < .05), whereas IED rates showed nonsignificant trends. Ten patients demonstrated FOs or seizures, and 12 showed IEDs. MSI of IEDs demonstrated consistent accuracy across vigilance states, with median Euclidean distances of 12.74 mm (interquartile range [IQR] = 22.74) in wake and 8.34 mm (IQR = 27.58) in sleep, and no systematic amplitude or spatial extent changes. Wavelet-MEM enabled frequency-specific source imaging, with FOs and seizures localizing concordantly to FCD lesions in five of seven and seven of eight patients, respectively. SIGNIFICANCE:Daytime sleep MEG recordings are clinically feasible and significantly enhance the detection of seizures (37% of patients) and FOs compared to wakefulness. Sleep protocols enable noninvasive capture of ictal patterns-the gold standard for epileptogenic zone localization-alongside increased FO rates. These findings support incorporating sleep into standard MEG protocols for presurgical epilepsy evaluation.

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.

Pathogenic variants in GABAA receptor subunit genes (GABR*) are important contributors to rare and common genetic epilepsies. Here, we present a comprehensive analysis of variants in GABRB1, which encodes the GABAA receptor β1 subunit, by revealing their functional implications, establishing genotype-phenotype correlations and evaluating treatment response. Clinical information on individuals carrying a GABRB1 variant was obtained through an international collaboration and literature review. Our cohort included 19 individuals (7 males, 12 females) from 15 families harbouring 13 different GABRB1 variants (11 missense, 1 indel, 1 stop). Functional analysis was performed using two-electrode voltage-clamp recordings in Xenopus laevis oocytes. For all 11 missense variants, α1β1γ2 GABAA receptors with a single mutant β1 subunit were used. Four missense variants were selected for further functional analysis using α5β1γ2 GABAA receptors with two mutant β1 subunits. Gain-of-function (GoF) effects, characterized by increased GABA-sensitivity, were observed for eight missense variants. Loss-of-function (LoF) effects were observed for one variant and no functional effects for two variants. Clinically, GoF variants were only observed in individuals with severe early-onset disease, including profound intellectual disability, hypotonia and early mortality. Additionally, cortical visual impairment, dysmorphisms and cortical atrophy were exclusive to this cohort. By integrating previously reported clinical data for variants in other GABR* genes, we validated that these features were associated with GoF variants more broadly. The only LoF variant was identified in a nuclear family with the relatively milder syndrome of genetic epilepsy with febrile seizures plus. Seizures were therapy-resistant in all individuals with GoF variants and a single individual with a LoF variant. The GABAergic anti-seizure medication (ASM) vigabatrin caused life-threatening side-effects in two individuals with GoF variants, while the sodium-channel blocker (SCB) lamotrigine exacerbated seizures in a single individual carrying a LoF variant. By integrating data from literature on all GABR* variants, we observed a potential dichotomy in treatment responses: GABAergic and broad-spectrum ASMs, such as valproate and levetiracetam, were more effective for individuals with LoF variants in GABR* genes, while SCBs showed greater benefit for GoF variants. Additionally, there is an increased risk of adverse effects of SCBs in LoF and vigabatrin in GoF variants. Our results highlight the importance of functional characterization of variants and clinical predictors in guiding treatment strategies for individuals with GABRB1 and other GABR* variants, although larger prospective studies are needed to confirm these observations.

The KCNA2 gene encodes the voltage-gated potassium channel Kv1.2, which is essential for repolarization of action potential. The R294H variant in KCNA2 represents the only potassium channel gene variant linked to hereditary spastic paraplegia (HSP) to date. However, this variant has been observed exclusively in heterozygous individuals. Here, we generated a homozygous KCNA2 R294H (c.881G > A) induced pluripotent stem cell (iPSC) line from a healthy individual iPSC line. The variant was introduced into both alleles using the CRISPR/Cas9 system. The resulting iPSC line has a normal karyotype, expresses key pluripotency markers, and is able to differentiate into all three germ layers.

ObjectiveEpilepsy is considered as a network disorder of interacting brain regions. The propagation of local epileptic activity from the seizure onset zone (SOZ) along neuronal networks determines the semiology of seizures. However, in highly interconnected brain regions such as the insula, the association between the SOZ and semiology is blurred necessitating invasive stereoelectroencephalography (SEEG). Normative connectomes on MRI data enable to link different symptoms and lesion locations to a common functional network. The present study applied connectomics to disentangle epilepsy networks from insular SEEG recordings and to describe their relationship to seizure semiology.MethodsWe retrospectively extracted functional networks by normative connectome analysis from 118 insular contacts depicting epileptic discharges during SEEG in 20 epilepsy patients. The resulting epilepsy networks were correlated to the corresponding semiology by voxel-wise regression and multivariate analyses of variances.ResultsEpileptic foci were found in the posterior insula for somatosensory, other sensory and motor seizures, while cognitive and autonomic symptoms were related to the anterior insula. We identified insular connections to the superior temporal gyrus and heschl gyrus in sensory seizures and projections to the somatosensory cortex in somatosensory seizures. Insula-basal ganglia pathways were found in cognitive seizure manifestations, while insular connectivity to fronto-basal regions were strongest in patients with autonomic seizures.ConclusionThe semiology of seizures is mirrored in the functional connectivity of insular epileptic discharges. Combining SEEG and connectomics could provide additional information about seizure propagation within the epilepsy network and might enable new treatment options in the future like deep brain stimulation.

Objective: Genetic generalized epilepsies (GGEs) comprise the most common genetically determined epilepsy syndromes, following a complex mode of inheritance. Although many important common and rare genetic factors causing or contributing to these epilepsies have been identified in the past decades, many features of the genetic architecture are still insufficiently understood. This study integrates genome-wide association study (GWAS) data from the International League Against Epilepsy Consortium on Complex Epilepsies with transcriptome-wide association studies to identify genes whose genetically regulated expression levels are associated with epilepsy. Methods: To achieve this, we used multiple computational approaches, including MAGMA, a tool for gene analysis of GWAS data, and its derivatives E-MAGMA and H-MAGMA, to improve gene mapping accuracy by utilizing tissue-specific expression and chromatin interaction data. Furthermore, we developed ME-MAGMA to incorporate methylation quantitative trait loci data, providing insights into epigenetic factors. Results: We identified a total of 897 false discovery rate-corrected (<.05) candidates. These include voltage-gated calcium channels, voltage-gated potassium channels, and other genes such as NPRL2, CACNB2, and KCNT1 associated with epilepsy pathogenesis that act as key players in neuronal communication and signaling in the brain. Significance: In this study, we propose new candidate genes to expand the dataset of potential epilepsy-causing genes. Further research on these genes may enhance our understanding of the complex regulatory mechanisms underlying GGE and other types of epilepsy, potentially revealing targets for therapeutic intervention.

OBJECTIVE:Pathogenic ANKH variants are a known cause of chondrocalcinosis (Online Mendelian Inheritance in Man [OMIM] #118600) and craniometaphyseal dysplasia (OMIM #123000). Here, we describe the phenotype and genotype of autosomal dominant infantile epilepsy caused by a c.-11C>T change upstream of the gene's normal ATG initiation codon of ANKH in a family of southern Italian descent; we correlate the phenotype with known epilepsy syndromes and provide the first evidence of recurrence of this particular ANKH variant. METHODS:Phenotyping and genotyping (short-read exome/genome sequencing) was performed on six members of a family with self-limited familial infantile epilepsy (SeLFIE). RESULTS:We describe a family with six individuals who presented with infantile onset epilepsy. All affected family members experienced focal and/or bilateral tonic-clonic seizures, sometimes triggered by fever or infection, with seizure onset predominantly before the age of 2 years. Patients responded well to antiseizure medication, and seizures resolved completely before the age of 4 years. Short-read genome/exome sequencing and comparative bioinformatic analysis of the variants of five affected individuals and one unaffected individual revealed ANKH c.-11C>T as the causative pathogenic variant in this family, segregating with the disease. SIGNIFICANCE:To our knowledge, we report the second family with autosomal dominant epilepsy caused by an ANKH c.-11C>T variant. The pediatric phenotype closely resembles that of the previously reported British family, suggesting low phenotypic heterogeneity, and aligns with SeLFIE. ANKH-associated epilepsy should be considered in SeLFIE, especially in cases with a family history of chondrocalcinosis or recurrent acute joint pain episodes.