De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP

Krishna R. Veeramah, Janelle E. O'Brien, Miriam H. Meisler, Xiaoyang Cheng, Sulayman D. Dib-Hajj, Stephen G. Waxman, Dinesh Talwar, Santhosh Girirajan, Evan E. Eichler, Linda L. Restifo, Robert P. Erickson, Michael F. Hammer

Research output: Contribution to journalArticle

215 Citations (Scopus)

Abstract

Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.

Original languageEnglish (US)
Pages (from-to)502-510
Number of pages9
JournalAmerican Journal of Human Genetics
Volume90
Issue number3
DOIs
StatePublished - Mar 9 2012

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Brain Diseases
Sodium Channels
Genome
Mutation
Epilepsy
Voltage-Gated Sodium Channels
Genetic Association Studies
Missense Mutation
Ataxia
Autistic Disorder
Sudden Death
Nervous System Diseases
Intellectual Disability
Genes
Seizures
Sodium
Phenotype
Neurons
Brain

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Veeramah, Krishna R. ; O'Brien, Janelle E. ; Meisler, Miriam H. ; Cheng, Xiaoyang ; Dib-Hajj, Sulayman D. ; Waxman, Stephen G. ; Talwar, Dinesh ; Girirajan, Santhosh ; Eichler, Evan E. ; Restifo, Linda L. ; Erickson, Robert P. ; Hammer, Michael F. / De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 3. pp. 502-510.
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abstract = "Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.",
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Veeramah, KR, O'Brien, JE, Meisler, MH, Cheng, X, Dib-Hajj, SD, Waxman, SG, Talwar, D, Girirajan, S, Eichler, EE, Restifo, LL, Erickson, RP & Hammer, MF 2012, 'De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP', American Journal of Human Genetics, vol. 90, no. 3, pp. 502-510. https://doi.org/10.1016/j.ajhg.2012.01.006

De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. / Veeramah, Krishna R.; O'Brien, Janelle E.; Meisler, Miriam H.; Cheng, Xiaoyang; Dib-Hajj, Sulayman D.; Waxman, Stephen G.; Talwar, Dinesh; Girirajan, Santhosh; Eichler, Evan E.; Restifo, Linda L.; Erickson, Robert P.; Hammer, Michael F.

In: American Journal of Human Genetics, Vol. 90, No. 3, 09.03.2012, p. 502-510.

Research output: Contribution to journalArticle

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T1 - De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP

AU - Veeramah, Krishna R.

AU - O'Brien, Janelle E.

AU - Meisler, Miriam H.

AU - Cheng, Xiaoyang

AU - Dib-Hajj, Sulayman D.

AU - Waxman, Stephen G.

AU - Talwar, Dinesh

AU - Girirajan, Santhosh

AU - Eichler, Evan E.

AU - Restifo, Linda L.

AU - Erickson, Robert P.

AU - Hammer, Michael F.

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Y1 - 2012/3/9

N2 - Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.

AB - Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.

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