Aug 2026· Journal of Medical Genetics· 0 citations· 39 references
Medicine
TL;DR
CACNA1C is potentially a candidate causative gene of focal epilepsy and the genotype-phenotype correlation of CACNA1C helps explain phenotypic heterogeneity.
Abstract
Purpose
CACNA1C variants have been identified in cardiac arrhythmias and developmental disorders (DD). Here, we aimed to explore the association between CACNA1C and epilepsy and the mechanism underlying phenotypic heterogeneity.
Methods
Trio-based whole-exome sequencing was performed in patients with focal epilepsy. Genes with recurrently identified variants were selected for further studies.
Results
Three de novo CACNA1C variants were identified in three patients with focal epilepsy. All variants presented no minor allele frequency in the Genome Aggregation Database, which was significantly lower than that of benign variants in the ClinVar database. The three de novo variants were evaluated as pathogenic or likely pathogenic variants according to the updated American College of Medical Genetics and Genomics (ACMG) classification. Two patients experienced infrequent seizures and became seizure free. The other patient had refractory epilepsy with DD and arrhythmia. Previously, 138 CACNA1C variants were reported to be associated with arrhythmias, of which 39 were classified as pathogenic or likely pathogenic; 30 variants were associated with DD, 19 of which were classified as pathogenic or likely pathogenic according to the updated ACMG classification. Further analysis indicated that null variants were more common in DD than in epilepsy (p=1.39×10-3) and arrhythmias (p=6.31×10-7). The epilepsy-associated variants were predominantly located in the voltage sensor region (p=9.03×10-3), whereas the arrhythmia-associated variants were mostly located in the linker region (p=2.13×10-4). There was a greater percentage of de novo variants in patients with epilepsy and DD than in those with arrhythmias (p=6.02×10-3; p=2.47×10-2).
Conclusion
CACNA1C is potentially a candidate causative gene of focal epilepsy. The genotype-phenotype correlation of CACNA1C helps explain phenotypic heterogeneity.
Clinical severity broadly tracks with the predicted structural/biophysical impact of the variant and Munc18‐1 abundance, providing a mechanistic clue for phenotypic heterogeneity in STXBP1‐related disorders.
Meng Xu, Xuan Guo, Zhi-Kui Wang et al.· CNS Neuroscience & Therapeut...· 0 citations
A pooled analysis delineates the phenotypic spectrum of ALG13-related epilepsy and emphasizes the prominence of the N107S hotspot variant, which is associated with more severe neurodevelopmental outcomes.
Song Su, Wenchao Zhang, Ying Ren et al.· Seizure· 0 citations
This study may expand the mutation and phenotypic spectrum of SETD1A-related disorders, establishing the relationship between SETD1A variants and isolated early-onset epilepsy without accompanying severe neurodevelopmental deficits, and highlighting the value of genetic testing in infants with unexplained epilepsy.
Rina Su, Lei Zhu, Lin Jiang et al.· Frontiers in Neuroscience· 0 citations
Abstract The KCNT1 gene encodes for a sodium-activated potassium channel involved in neuronal excitability. Since its initial description in 2012 in patients with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) and in Sleep-related Hypermotor Epilepsy (SHE), the associated phenotypic spectrum has broadened—encompassing other focal epilepsies and Developmental and Epileptic Encephalopathies (DEEs)—and has included extra-neurological features. We aimed to characterize the neurological outcomes, extra-neurological features, mortality and genotype-phenotype correlations expanding the follow-up of the reported cases with KCNT1 variants. A comprehensive literature review was performed to identify all reported cases of KCNT1 pathogenic or likely pathogenic variants. Corresponding authors were contacted to obtain updated clinical data, including current vital status, epilepsy progression, extra-neurological features, cognitive and psychiatric status. The entire dataset, including updated data from the literature, was combined for subsequent analyses. A total of 316 patients from 88 publications were included. Follow-up data were obtained for 60 patients (from 28 papers and 11 countries), increasing the median age at last assessment from 4.4 to 6.0 years. 181 patients had an EIMFS phenotype, 62 had SHE, and 59 had various DEEs. Five individuals were asymptomatic parents, six had other focal epilepsies, and three had other phenotypes. Extra-neurological features were predominantly observed in patients with EIMFS and DEE, notably systemic-to-pulmonary collateral arteries, other vascular or cardiac malformations and various respiratory, orthopaedic or gastrointestinal disorders. The main cause of death was pulmonary complications (haemorrhage or infection). Genotype–phenotype correlations revealed a trend for variants in the first regulator of conductance of potassium (RCK1) domain to associate with EIMFS/non-EIMFS DEE, while SHE-associated variants were predominantly located in the second regulator of conductance of potassium (RCK2) domain. Additionally, variants p.Arg474Cys may confer increased risk for vascular malformations, but the issue appears to be broader, and systematic screening of patients carrying pathogenic KCNT1 variants would allow us to better define this risk. This study offers a comprehensive understanding of the clinical spectrum and genotype-phenotype correlation in KCNT1-related disorders. This study has inherent biases related to the retrospective collection of already published data and underscores the need to develop multisource data methodologies and registries to reduce follow-up loss in real-world data collections based on health records.
Mathilde Gras, Gaëlle Quentin-Romand, N. Chemaly et al.· Brain Communications· 0 citations
This is the second report of autosomal recessive epilepsy associated with biallelic CACNB4 variants and genetic investigations play a crucial role in identifying mutation hotspots, facilitating more accurate diagnoses and enhancing the design of diagnostic panels for early detection.
OBJECTIVE
SCN1A variants are the primary genetic cause of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy characterized by early-onset prolonged seizures and progressive neurodevelopmental impairment. Early molecular diagnosis may influence treatment decisions and clinical outcomes. To characterize the molecular spectrum of SCN1A variants and describe the associated clinical and therapeutic features in children with suspected DS.
METHODS
This retrospective study included children evaluated between 2018 and 2020 with clinical suspicion of DS or febrile seizures with epilepsy who were referred for SCN1A genetic testing. Next-generation sequencing was used to detect sequence variants, complemented by multiplex ligation-dependent probe amplification for copy number analysis. A total of 60 patients were screened, and 18 patients carrying pathogenic or likely pathogenic SCN1A variants and fulfilling clinical criteria for DS were included.
RESULTS
Eighteen patients were identified with heterozygous pathogenic or likely pathogenic SCN1A variants, including 6 novel variants. Segregation analysis demonstrated that all 15 tested patients had de novo variants. Seizure onset ranged from 2.5 to 8 months, predominantly before 6 months of age. Several patients were exposed to sodium channel-blocking agents prior to molecular confirmation, with seizure aggravation and subsequent treatment modification. All patients required multiple anti-seizure medications and showed varying degrees of neurodevelopmental impairment.
CONCLUSION
SCN1A-confirmed DS is associated with substantial seizure burden and neurodevelopmental morbidity. Delayed molecular diagnosis may lead to inappropriate treatment exposure and seizure worsening. Early genetic testing in infants with early-onset seizures may improve treatment selection and clinical outcomes.
Esma Şengenç, Şeyma Sönmez Şahin, A. Iscan et al.· Turkish archives of pediatri...· 0 citations