A novel inherited SCN1A mutation associated with different neuropsychological phenotypes: Is there a common core deficit?

Passamonti, Claudia; Petrelli, Cristina; Mei, Davide; Foschi, Nicoletta; Guerrini, Renzo; Provinciali, Leandro; Zamponi, Nelia

doi:10.1016/j.yebeh.2014.11.009

Cited by 21 publications

(16 citation statements)

References 19 publications

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“…In around 88% of epilepsy patients carrying rare SCN1A mutations, these arise de novo , whereas only 12% of the affected individuals inherit the mutation from a, usually unaffected, parent [ 4 ]. Patients with an identical mutation may express a broad spectrum of phenotypes even within a single large family ranging from unaffected, over GEFS+ to Dravet syndrome [ 7 , 8 ]. Most functional studies of disease-associated variants showed loss-of-function effects of SCN1A mutations [ 9 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

et al. 2016

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ObjectiveThe SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic.MethodsWe screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients.Results and InterpretationWe identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10−4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

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Section: Introductionmentioning

confidence: 99%

Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

et al. 2016

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“…The majority of neuropsychological studies in people with genetic epilepsy have been conducted in pediatric populations, reflecting the general predominance of genetic studies in children [6][7][8][9]. Studies that have looked for a common neuropsychological deficit in people with inherited gene mutations have had mixed results to date, with some reporting very specific relationships between neuropsychological function and genetic variables [10][11][12] and others finding very few clinical correlations [13].…”

Section: Neuropsychological Characteristics Of Genetic Epilepsies In mentioning

confidence: 99%

“…Passamonti et al [13] examined the neuropsychological functions of thirteen patients, across three generations of a family who had a novel inherited splicing mutation of the SCNIA gene. There was very little homogeneity in the group, with half having no history of epilepsy, a nor-mal EEG and cognitive profile, while the others had a wide variety of clinical symptoms including generalized epilepsy, Dravet syndrome, and focal epilepsy.…”

Section: Neuropsychological Characteristics Of Genetic Epilepsies In mentioning

confidence: 99%

“…However, the new classification introduces the reconceptualization of focal and generalized seizures arising from a disease of brain net-works. As observed in the call for papers for this special issue, 'this change brings a fundamental shift to our thinking about the co-morbidities of epilepsy' [13]. As part of the network approach, changes in cognition and behavior are seen as a fundamental manifestation of the diseased network [16].…”

Section: Neuropsychological Characteristics Of Genetic Epilepsies In mentioning

confidence: 99%

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Reprint of: The new approach to epilepsy classification: Cognition and behavior in adult epilepsy syndromes

Baxendale

Thompson

2016

Epilepsy & Behavior

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The revised terminology and concepts for the organization of seizures and epilepsy proposed by the ILAE Commission on Classification and Terminology in 2010 allows for a number of new opportunities in the study of cognition and behavior in adults. This review examines the literature that has looked for behavioral and cognitive correlates of the newly recognized genetic epilepsies in adults. While some studies report clear cognitive phenotypes associated with specific genetic mutations in adults with epilepsy, others report remarkable clinical heterogeneity. In the second part of this review, we discuss some of the factors that may influence the findings in this literature. Cognitive function is the product of both genetic and environmental influences. Neuropsychological phenotypes under direct genetic influence may be wider and more subtle than specific deficits within discreet cognitive domains and may be reflected in broader, multidimensional measures of cognitive function than those tapped by scores on standardized tests of function. Future studies must be carefully designed to reflect these factors. It is also imperative that studies with negative findings are assigned as much value as those with positive results and published accordingly. This article is part of a Special Issue titled "The new approach to classification: Rethinking cognition and behavior in epilepsy".

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“…The association of SCN1A with multiple phenotypes may be partly explained by the varying effects of different pathogenic variants: variants that cause a complete loss of function (LoF) of the channel are virtually always associated with severe phenotypes, whereas variants that cause milder disturbances are usually found in milder phenotypes (Meng et al, ). However, this does not fully explain the variability that is observed in SCN1A related phenotypes: varying phenotypes have been associated with the exact same variant, even within families, and Dravet syndrome patients with similar LoF variants may show very different clinical outcomes (Akiyama, Kobayashi, Yoshinaga, & Ohtsuka, ; Depienne et al, ; Guerrini et al, ; Harkin et al, ; Jansen et al, ; Mahoney et al, ; Passamonti et al, ; Pineda‐Trujillo et al, ; Suls et al, ). Several modifying factors have already been proven or suggested to have an influence on these outcomes, such as mosaicism for the pathogenic SCN1A variants, the presence of variants in modifier genes and environmental factors such as anti‐epileptic treatment (Ceulemans, ; Depienne et al, ; Gennaro et al, ; Guerrini et al, ; Lange, Gunning, et al, ; Lange, Koudijs, et al, ; Marini, Mei, Helen Cross, & Guerrini, ).…”

Section: Introductionmentioning

confidence: 99%

Influence of common SCN1A promoter variants on the severity of SCN1A‐related phenotypes

Lange

Weuring

Slot

et al. 2019

Molec Gen & Gen Med

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Background Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants. Methods Five different SCN1A promoter‐haplotypes were functionally assessed in SH‐SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter‐region of their unaffected allele were investigated. Results All non‐wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter‐region (65%–80%, p = 0.039–0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter‐haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes. Conclusion The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter‐haplotypes.

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A novel inherited SCN1A mutation associated with different neuropsychological phenotypes: Is there a common core deficit?

Cited by 21 publications

References 19 publications

Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

Reprint of: The new approach to epilepsy classification: Cognition and behavior in adult epilepsy syndromes

Influence of common SCN1A promoter variants on the severity of SCN1A‐related phenotypes

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