Autosomal dominant SCN8A mutation with an unusually mild phenotype

Anand, Geetha; Collett-White, F.; Orsini, Alessandro; Thomas, Sharon E.; Jayapal, S.; Trump, N; Zaiwalla, Zenobia; Jayawant, Sandeep

doi:10.1016/j.ejpn.2016.04.015

Cited by 45 publications

(56 citation statements)

References 6 publications

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“…N1877S is predicted to be damaging by PolyPhen-2 and SIFT. SCN8A p.N1877S has not been observed in the ExAC database but has been reported twice in ClinVar (once as a VUS and once as a likely pathogenic de novo variant) and has recently been reported in a father and son with early-onset epilepsy without cognitive impairment (Anand et al, 2016). This additional instance of parental transmission and milder epilepsy presentation associated with the same SCN8A variant again lends support to the prediction that this is a pathogenic variant.…”

Section: Resultsmentioning

confidence: 99%

“…However, neither individual exhibited cognitive impairment. The son’s EEG showed background slowing and disorganization with active focal epileptiform discharges, but his seizures were controlled on carbamazepine (Anand et al, 2016). Here we report an additional family segregating the SCN8A p.N1877S variant.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to these two families, SCN8A p.N1877S has also been observed de novo in at least two other epilepsy patients with developmental delay and intellectual disability. Anand and colleagues speculated that additional modifying genetic variants may explain the reduced disease severity in their two cases, although no candidates were revealed by the gene panel analysis (Anand et al, 2016). In the family presented here, variants in additional genes were uncovered from the gene panel analysis.…”

Section: Discussionmentioning

confidence: 99%

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De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis

Butler

Silva

Shafir³

et al. 2017

Epilepsy Research

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Objectives To determine the incidence of pathogenic SCN8A variants in a cohort of epilepsy patients referred for clinical genetic testing. We also investigated the contribution of SCN8A to autism spectrum disorder, intellectual disability, and neuromuscular disorders in individuals referred for clinical genetic testing at the same testing laboratory. Methods Sequence data from 275 epilepsy panels screened by Emory Genetics Laboratory were reviewed for variants in SCN8A. Additional cases with variants in SCN8A were ascertained from other testing laboratories. Parental samples were tested for variant segregation and clinical histories were examined. SCN8A variants detected from gene panel analyses for autism spectrum disorder, intellectual disability, and neuromuscular disorders were also examined. Results Five variants in SCN8A were identified in five individuals with epilepsy. Three variants were de novo, one was inherited from an affected parent, and one was inherited from an unaffected parent. Four of the individuals have epilepsy and developmental delay/intellectual disability. The remaining individual has a milder epilepsy presentation without cognitive impairment. We also identified an amino acid substitution at an evolutionarily conserved SCN8A residue in a patient who was screened on the autism spectrum disorder panel. Additionally, we examined the distribution of pathogenic SCN8A variants across the Nav1.6 channel and identified four distinct clusters of variants. These clusters are primarily located in regions of the channel that are important for the kinetics of channel inactivation. Conclusions Variants in SCN8A may be responsible for a spectrum of epilepsies as well as other neurodevelopmental disorders without seizures. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis

Butler

Silva

Shafir³

et al. 2017

Epilepsy Research

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“…5614C > T, p.Arg1872Trp52,200,884C-terminalDisease causingProbably damagingReported [9, 14]Pateint 4c. 423G > A, p.Gly1475Arg52,184,185DIIIS6-DIVS1 loopDisease causingProbably damagingReported [15]Patient 5c.5630A > G, p.Asn1877Ser52,200,900C-terminalDisease causingPossibly damagingReported [15, 16]Patient 6p.2671G > A, p.Val891Met52,159,581DIIS5Disease causingProbably damaging Novel Pedigreec.4793 T > C, p.Val1598Ala52,188,423DIVS3Disease causingProbably damaging Novel The positions of the mutations on chromosome 12 refer to the reference sequence that was retrieved from the NCBI database (build 37) …”

Section: Resultsmentioning

confidence: 99%

SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures

et al. 2017

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Background SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations.MethodsTo identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained.ResultsA heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence.ConclusionsOur findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.Electronic supplementary materialThe online version of this article (10.1186/s12881-017-0460-1) contains supplementary material, which is available to authorized users.

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“…Previous studies showed that SCN8A and CHRNA2 mutations was identified in sporadic families with BFIE [34,35]. These two genes are also included in our gene panel.…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

et al. 2017

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Benign familial epilepsies that present themselves in the first year of life include benign familial neonatal epilepsy (BFNE), benign familial neonatal-infantile epilepsy (BFNIE) and benign familial infantile epilepsy (BFIE). We used Sanger sequencing and targeted next-generation sequencing to detect gene mutations in a Chinese cohort of patients with these three disorders. A total of 79 families were collected, including 4 BFNE, 7 BFNIE, and 68 BFIE. Genetic testing led to the identification of gene mutations in 60 families (60 out of 79, 75.9%). A total of 42 families had PRRT2 mutations, 9 had KCNQ2 mutations, 8 had SCN2A mutations, and 1 had a GABRA6 mutation. In total three of four BFNE families were detected with KCNQ2 mutations. Mutations were detected in all BFNIE families, including 3 KCNQ2 mutations, 3 SCN2A mutations, and 1 PRRT2 mutation. Gene mutations were identified in 50 out of 68 BFIE families (73.5%), including 41 PRRT2 mutations (41 out of 68, 60.3%), 5 SCN2A mutations, 3 KCNQ2 mutations, and 1 GABRA6 mutation. Our results confirmed that mutations in KCNQ2, SCN2A, and PRRT2 are major genetic causes of benign familial epilepsy in the first year of life in the Chinese population. KCNQ2 is the major gene related to BFNE. PRRT2 is the main gene responsible for BFIE.

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Autosomal dominant SCN8A mutation with an unusually mild phenotype

Cited by 45 publications

References 6 publications

De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis

De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis

SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures

Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort

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