Clinical implications of <i><scp>SCN</scp>1A</i> missense and truncation variants in a large Japanese cohort with Dravet syndrome

Ishii, Atsushi; Watkins, Joseph C.; Chen, Debbie; Hirose, Shinichi; Hammer, Michael F.

doi:10.1111/epi.13639

Cited by 58 publications

(86 citation statements)

References 26 publications

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“…Indeed, from our previous work on Dravet syndrome [15], we found PolyPhen-2 to be the most reliable predictor. To certify this formally, we compare the performance of the other three aforementioned pathogenicity scores against PolyPhen-2 using the area under the curve (AUC) for the receiver-operating characteristic.…”

Section: Methodsmentioning

confidence: 88%

“…We chose 22 subjects at opposite ends of a phenotypic distribution (11 mild and 11 severe) from a large cohort of Japanese patients with SCN1A truncation variants [15]. During the course of the study the two youngest patients in the mild category progressed to a more severe phenotype, leaving 9 individuals in the mild group.…”

Section: Resultsmentioning

confidence: 99%

“…We chose to restrict our study to epilepsy patients carrying a truncation mutation in SCN1A to control for the effect of ‘mutation type’ on clinical outcome. Truncation mutations anywhere in the SCN1A gene other than in exon 26 are predicted to result in nonsense mediated RNA decay and haploinsufficiency [15]. Unlike missense variants that are present in different functional domains of the channel and that result in different amino acid substitutions, truncation mutations can be considered a single “genetic phenotype.” Barring the effects of other factors, truncation mutations are expected to be associated with a more homogeneous clinical outcome [15].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, there are no known modifiers that completely protect individuals with SCN1A truncation mutations, and no SCN1A truncation variants are present in large public databases of healthy individuals (i.e., without childhood epilepsy). Because all patients with DS tend to progress from a mild to a severe cognitive phenotype [15], the difference between our phenotypic groups—and hence what putative modifiers may be acting upon—are processes that influence the rate of cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

“…We previously described a cohort of 285 patients with SCN1A -positive Dravet Syndrome [15] for which we had detailed clinical data that was collected by pediatric neurologists between September 2014 and September 2015. Referring physicians classified 176 of these 285 DS patients, as well as 12 other epilepsy patients with SCN1A variants, in one of five categories (normal, border, mild, moderate and severe) on the basis of intellectual and developmental quotient (IQ and DQ) assessment tests (Tanaka-Binet, WISC-IV, Enjoji Scale of Infant Analytical Development, Kyoto Scale of Psychological Development 2001, Kinder Infant Development Scale, and Tsumori-Inage Infant Mental tests), which varied by age of child.…”

Section: Methodsmentioning

confidence: 99%

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Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome

et al. 2017

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Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i.e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.

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Section: Methodsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome

et al. 2017

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Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe

et al. 2021

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Dravet syndrome (DS) is a severe, rare, and complex developmental and epileptic encephalopathy affecting 1 in 16 000 live births and characterized by a drug-resistant epilepsy, cognitive, psychomotor, and language impairment, and behavioral disorders. Evidence suggests that optimal treatment of seizures in DS may improve outcomes, even though neurodevelopmental impairments are the likely result of both the underlying genetic variant and the epilepsy. We present an updated guideline for DS diagnosis and treatment, taking into consideration care of the adult patient and nonpharmaceutical therapeutic options for this disease. This up-to-date guideline, which is based on an extensive review of the literature and culminates with a new treatment algorithm for DS, is a European consensus developed through a survey involving 29 European clinical experts in DS. This guideline will serve professionals in their clinical practice and, as a consequence, will benefit DS patients and their families.

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SCN1A variants from bench to bedside—improved clinical prediction from functional characterization

et al. 2019

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Variants in the SCN1A gene are associated with a wide range of disorders including genetic epilepsy with febrile seizures plus (GEFS+), familial hemiplegic migraine (FHM), and the severe childhood epilepsy Dravet syndrome (DS). Predicting disease outcomes based on variant type remains challenging. Despite thousands of SCN1A variants being reported, only a minority has been functionally assessed.We review the functional SCN1A work performed to date, critically appraise electrophysiological measurements, compare this to in silico predictions, and relate our findings to the clinical phenotype.Our results show, regardless of the underlying phenotype, that conventional in silico software correctly predicted benign from pathogenic variants in nearly 90%, however was unable to differentiate within the disease spectrum (DS vs. GEFS+ vs. FHM). In contrast, patch-clamp data from mammalian expression systems revealed functional differences among missense variants allowing discrimination between disease severities. Those presenting with milder phenotypes retained a degree of channel function measured as residual whole-cell current, whereas those without any wholecell current were often associated with DS (p = .024).These findings demonstrate that electrophysiological data from mammalian expression systems can serve as useful disease biomarker when evaluating SCN1A variants, particularly in view of new and emerging treatment options in DS. K E Y W O R D SDravet syndrome, electrophysiology, familial hemiplegic migraine, functional testing, GEFS+, patch-clamp, SCN1A *Andreas Brunklaus and Stephanie Schorge contributed equally to this study.

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Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome

Cited by 58 publications

References 26 publications

Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome

Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome

Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe

SCN1A variants from bench to bedside—improved clinical prediction from functional characterization

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