Modifier genes in SCN1A‐related epilepsy syndromes

Lange, Iris; Mulder, Flip; Slot, Ruben van ‘t; Sonsma, Anja C. M.; Kempen, Marjan J. A. van; Nijman, Isaäc J.; Ernst, Robert F; Knoers, Nine V A M; Brilstra, Eva H.; Koeleman, Bobby P. C.

doi:10.1002/mgg3.1103

Cited by 20 publications

(13 citation statements)

References 65 publications

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“…However, there have been reports of Dravet syndrome caused by SCN1A variants inherited from mildly affected parents, as well as some individuals with de novo loss-of-function or premature truncation variants that presented with milder phenotypes, like generalized epilepsy with febrile seizures plus (GEFS + ) (Depienne et al 2010 , 2009 ; Goldberg-Stern et al 2014 ; Guerrini et al 2010 ; Nabbout et al 2003 ; Osaka et al 2007 ; Yordanova et al 2011 ; Yu et al 2010 ). This variable expressivity suggests that disease severity is influenced by additional factors, which may include genetic modifiers (de Lange et al 2020 ; Hammer et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Fine mapping and candidate gene analysis of a dravet syndrome modifier locus on mouse chromosome 11

et al. 2022

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Pathogenic variants in SCN1A result in a spectrum of phenotypes ranging from mild febrile seizures to Dravet syndrome, a severe infant-onset epileptic encephalopathy. Individuals with Dravet syndrome have developmental delays, elevated risk for sudden unexpected death in epilepsy (SUDEP), and have multiple seizure types that are often refractory to treatment. Although most Dravet syndrome variants arise de novo, there are cases where an SCN1A variant was inherited from mildly affected parents, as well as some individuals with de novo loss-of-function or truncation mutations that presented with milder phenotypes. This suggests that disease severity is influenced by other factors that modify expressivity of the primary mutation, which likely includes genetic modifiers. Consistent with this, the Scn1a+/− mouse model of Dravet syndrome exhibits strain-dependent variable phenotype severity. Scn1a+/− mice on the 129S6/SvEvTac (129) strain have no overt phenotype and a normal lifespan, while [C57BL/6Jx129]F1.Scn1a+/− mice have severe epilepsy with high rates of premature death. Low resolution genetic mapping identified several Dravet syndrome modifier (Dsm) loci responsible for the strain-dependent difference in survival of Scn1a+/− mice. To confirm the Dsm5 locus and refine its position, we generated interval-specific congenic strains carrying 129-derived chromosome 11 alleles on the C57BL/6J strain and localized Dsm5 to a 5.9 Mb minimal region. We then performed candidate gene analysis in the modifier region. Consideration of brain-expressed genes with expression or coding sequence differences between strains along with gene function suggested numerous strong candidates, including several protein coding genes and two miRNAs that may regulate Scn1a transcript.

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Section: Introductionmentioning

confidence: 99%

Fine mapping and candidate gene analysis of a dravet syndrome modifier locus on mouse chromosome 11

et al. 2022

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“…Thus, the same variant may lead to GEFS+ or in few cases to DS [Helbig, 2015;Scheffer and Nabbout, 2019]. It has been reported that the phenotypic heterogeneity observed in cases with the same variant may be associated with modifier genes and somatic mosaicism [Goldberg-Stern et al, 2014;Myers CT et al, 2018;de Lange et al, 2020]. Wholeexome sequencing analyses performed in cases with variations in the SCN1A gene showed that patients had a milder clinical picture when they had variations in other epilepsy-associated genes such as SCN8A, SCN9A, MOCS2, RAI1, and KMT2A in addition to the variation in SCN1A [de Lange et al, 2020].…”

Section: Discussionmentioning

confidence: 99%

“…This combination could perhaps explain the milder phenotypes. Furthermore, cases with variations in KCNQ3 and TSC2 genes exhibited a more severe epilepsy phenotype [de Lange et al, 2020]. Moreover, the parents of DS cases with de novo truncation variants in the SCN1A gene have somatic mosaicism, and they show a milder phenotype [de Lange et al, 2018].…”

Section: Discussionmentioning

confidence: 99%

Genetic Landscape of SCN1A Variants in a Turkish Cohort with GEFS+ Spectrum and Dravet Syndrome

et al. 2022

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Introduction: The α subunit of voltage-gated sodium channels in mammals is encoded by 9 different genes, and variations in the SCN1A, SCN2A, SCN3A, and SCN8A genes highly expressed in the CNS have been associated with epilepsy phenotypes. This study aimed at investigating the frequency of SCN1A gene variations in Dravet syndrome (DS) and GEFS+ spectrum phenotype cases and discussing the molecular results in the context of genotype-phenotype correlation. Methods: Fifteen patients diagnosed with DS and 54 patients meeting the GEFS+ spectrum criteria were included in this study. All patients were evaluated by next-generation sequencing and multiplex ligation-dependent probe amplification using an SCN1A gene commercial kit. Results: A total of 17 different variants were detected in 18 index cases (26%), of which 7 were novel variations (p.M1R, p.M147T, p.I767L, p.N1391Ifs*5, p.R1886G, p.E1915G, p.R1933Q). Of the 18 cases with variation in the SCN1A gene, 12 had DS and 6 had GEFS+ phenotype. The variations were de novo in all DS cases and in 1 case with a GEFS+ phenotype; in 5 GEFS+ cases, the variant was inherited from the affected parent. Discussion: This study contributes to the variation spectrum in cases with DS and GEFS+ phenotype with the novel variants detected. SCN1A genetic analysis can help in determining whether antiseizure medication should be selected or avoided in cases with variations. The elucidation of the molecular etiology makes it possible to provide the family with effective genetic counseling for future pregnancies.

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“…[19][20][21] Indeed genetic background has been shown to influence disease severity in DS, 7 whereas evidence for specific modifier genes has emerged. 18 In some cases variants in other ion channels have been shown to be associated intra-familial variability in phenotype severity, for example, in SCN9A, 22 CACNA1A, 23 CACNB4, 24 and KCNQ2. 7 Here we study a four-generation family kindred in which a single pathogenic variant is segregating among multiple members with a range of severities ranging from unaffected carriers to febrile seizures to DS.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing and co‐expression analysis identify an SCN1A variant that modifies pathogenicity in a family with genetic epilepsy and febrile seizures plus

et al. 2022

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Objective Family members carrying the same SCN1A variant often exhibit differences in the clinical severity of epilepsy. This variable expressivity suggests that other factors aside from the primary sodium channel variant influence the clinical manifestation. However, identifying such factors has proven challenging in humans. Methods We perform whole exome sequencing (WES) in a large family in which an SCN1A variant (p.K1372E) is segregating that is associated with a broad spectrum of phenotypes ranging from lack of epilepsy, to febrile seizures and absence seizures, to Dravet syndrome. We assessed the hypothesis that the severity of the SCN1A‐related phenotype was affected by alternate alleles at a modifier locus (or loci). Results One of our top candidates identified by WES was a second variant in the SCN1A gene (p.L375S) that was shared exclusively by unaffected carriers of the K1372E allele. To test the hypothesized that L375S variant nullifies the loss‐of‐function effect of K1372E, we transiently expressed Nav1.1 carrying the two variants in HEK293T cells and compared their biophysical properties with the wild‐type (WT) variant, and then co‐expressed WT with K1372E or L375S with K1372E in equal quantity and tested the functional consequence. The data demonstrated that co‐expression of the L375S and K1372E alleles reversed the loss‐of‐function property brought by the K1372E variant, whereas WT‐K1372E co‐expression remained partial loss‐of‐function. Significance These results support the hypothesis that L375S counteracts the loss‐of‐function effect of K1372E such that individuals carrying both alleles in trans do not present epilepsy‐related symptoms. We demonstrate that monogenic epilepsies with wide expressivity can be modified by additional variants in the disease gene, providing a novel framework for the gene‐phenotype relationship in genetic epilepsies.

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Modifier genes in SCN1A‐related epilepsy syndromes

Cited by 20 publications

References 65 publications

Fine mapping and candidate gene analysis of a dravet syndrome modifier locus on mouse chromosome 11

Fine mapping and candidate gene analysis of a dravet syndrome modifier locus on mouse chromosome 11

Genetic Landscape of <b><i>SCN1A</i></b> Variants in a Turkish Cohort with GEFS+ Spectrum and Dravet Syndrome

Whole exome sequencing and co‐expression analysis identify an SCN1A variant that modifies pathogenicity in a family with genetic epilepsy and febrile seizures plus

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