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SCN9A should not be considered an epilepsy gene; Refuting a gene-disease association
(Wiley, 2025-06-10)
Ismael Ghanty
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PEREZ PALMA, EDUARDO ESTEBAN
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Camilo Villaman
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Daniel Stobo
;
Joseph Symonds
Objective The SCN9A gene is primarily expressed in nociceptive pathways within the peripheral nervous system, and pathogenic variants are associated with human pain disorders. In recent years, several studies have proposed SCN9A as a monogenic cause of epilepsy. Our objective was to critically appraise the SCN9A–epilepsy gene–disease relationship. Methods We assessed “epilepsy-associated” SCN9A variants from four sources: (1) the literature up to December 2023 (n = 27), (2) epilepsy patients referred for genetic testing at a regional service in Glasgow, UK over a 5-year period (n = 30), (3) the Human Genetics Mutation Database (n = 25), and (4) ClinVar (n = 1546). The latter two are genome-wide variant databases, accepting submissions from genetic laboratories and research groups. We checked whether each SCN9A variant is present in the Genome Aggregation Database (gnomAD) V4 (a reference population database for variant interpretation), and classified its pathogenicity based on the American College of Molecular Genetics and Genomics/Association of Molecular Pathologists guidelines. Results Only three SCN9A variants were classified as “likely pathogenic,” of which two were identified in healthy individuals in gnomAD. A total of 1540 of the 1546 SCN9A variants in ClinVar labeled as being associated with epilepsy were also reported in association with hereditary sensory and autonomic neuropathy. No further clinical data were provided in 1482 of these submissions. Significance There is no convincing genetic evidence to support SCN9A as a causative epilepsy gene. As such, the inclusion of SCN9A in epilepsy genetic testing panels should be reassessed. Research centers and genetic testing laboratories should be rigorous and consistent in their submissions to variant databases.
Scopus© Citations 3 4
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Congruence and discrepancy of interictal and ictal EEG with MRI lesions in focal epilepsies
(2011)
J. Rémi
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C. Vollmar
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ALEJANDRO DE MARINIS PALOMBO
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J. Heinlin
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A. Peraud
5Scopus© Citations 61
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Data-driven historical characterization of epilepsy-associated genes
(2023)
Marie Macnee
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PEREZ PALMA, EDUARDO ESTEBAN
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Javier A. López-Rivera
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Alina Ivaniuk
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Patrick May
1 1Scopus© Citations 28
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Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes
(2022)
Tobias Brünger
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PEREZ PALMA, EDUARDO ESTEBAN
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Ludovica Montanucci
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Michael Nothnagel
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Rikke S Møller
<jats:title>Abstract</jats:title> <jats:p>Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion-channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated.</jats:p> <jats:p>We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion-channel families. We collected and curated 3049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12 546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures.</jats:p> <jats:p>We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis centre and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and functional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1422 neurodevelopmental disorder pathogenic patient variants and 679 electrophysiological experiments, we show that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain versus loss-of-channel function.</jats:p> <jats:p>In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional readouts and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.</jats:p>
1Scopus© Citations 13 6
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Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice
(2022)
Dianalee McKnight
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Ana Morales
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Kathryn E. Hatchell
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Sara L. Bristow
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Joshua L. Bonkowsky
<jats:sec id="ab-noi220068-4"><jats:title>Importance</jats:title><jats:p>It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.</jats:p></jats:sec><jats:sec id="ab-noi220068-5"><jats:title>Objective</jats:title><jats:p>To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.</jats:p></jats:sec><jats:sec id="ab-noi220068-6"><jats:title>Design, Setting, and Participants</jats:title><jats:p>This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.</jats:p></jats:sec><jats:sec id="ab-noi220068-7"><jats:title>Exposures</jats:title><jats:p>Genetic test results.</jats:p></jats:sec><jats:sec id="ab-noi220068-8"><jats:title>Main Outcomes and Measures</jats:title><jats:p>Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.</jats:p></jats:sec><jats:sec id="ab-noi220068-9"><jats:title>Results</jats:title><jats:p>Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).</jats:p></jats:sec><jats:sec id="ab-noi220068-10"><jats:title>Conclusions and Relevance</jats:title><jats:p>Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.</jats:p></jats:sec>
3Scopus© Citations 70
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Muerte súbita en epilepsia
(2018)
Mauricio Velásquez
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ALEJANDRO DE MARINIS PALOMBO
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Evelyn Benavides
Scopus© Citations 2 1
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DOORS syndrome: Phenotype, genotype and comparison with coffin-siris syndrome
(2014)
Philippe M. Campeau
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Raoul C. Hennekam
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REPETTO LISBOA, MARIA GABRIELA
Scopus© Citations 37 24

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