SCN8A mutation in a child presenting with seizures and developmental delays

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Abstract

The SCN8A gene encodes the sodium voltage-gated channel alpha subunit 8. Mutations in this gene have been associated with early infantile epileptic encephalopathy type 13. With the use of whole-exome sequencing, a de novo missense mutation in SCN8A was identified in a 4-yr-old female who initially exhibited symptoms of epilepsy at the age of 5 mo that progressed to a severe condition with very little movement, including being unable to sit or walk on her own.

Most cited references 19

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Gene: a gene-centered information resource at NCBI

Garth R. Brown, Vichet Hem, Kenneth Katz … (2014)

The National Center for Biotechnology Information's (NCBI) Gene database (www.ncbi.nlm.nih.gov/gene) integrates gene-specific information from multiple data sources. NCBI Reference Sequence (RefSeq) genomes for viruses, prokaryotes and eukaryotes are the primary foundation for Gene records in that they form the critical association between sequence and a tracked gene upon which additional functional and descriptive content is anchored. Additional content is integrated based on the genomic location and RefSeq transcript and protein sequence data. The content of a Gene record represents the integration of curation and automated processing from RefSeq, collaborating model organism databases, consortia such as Gene Ontology, and other databases within NCBI. Records in Gene are assigned unique, tracked integers as identifiers. The content (citations, nomenclature, genomic location, gene products and their attributes, phenotypes, sequences, interactions, variation details, maps, expression, homologs, protein domains and external databases) is available via interactive browsing through NCBI's Entrez system, via NCBI's Entrez programming utilities (E-Utilities and Entrez Direct) and for bulk transfer by FTP.

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Performance comparison of Illumina and ion torrent next-generation sequencing platforms for 16S rRNA-based bacterial community profiling.

Stephen Salipante, Toana Kawashima, Christopher Rosenthal … (2014)

High-throughput sequencing of the taxonomically informative 16S rRNA gene provides a powerful approach for exploring microbial diversity. Here we compare the performances of two common "benchtop" sequencing platforms, Illumina MiSeq and Ion Torrent Personal Genome Machine (PGM), for bacterial community profiling by 16S rRNA (V1-V2) amplicon sequencing. We benchmarked performance by using a 20-organism mock bacterial community and a collection of primary human specimens. We observed comparatively higher error rates with the Ion Torrent platform and report a pattern of premature sequence truncation specific to semiconductor sequencing. Read truncation was dependent on both the directionality of sequencing and the target species, resulting in organism-specific biases in community profiles. We found that these sequencing artifacts could be minimized by using bidirectional amplicon sequencing and an optimized flow order on the Ion Torrent platform. Results of bacterial community profiling performed on the mock community and a collection of 18 human-derived microbiological specimens were generally in good agreement for both platforms; however, in some cases, results differed significantly. Disparities could be attributed to the failure to generate full-length reads for particular organisms on the Ion Torrent platform, organism-dependent differences in sequence error rates affecting classification of certain species, or some combination of these factors. This study demonstrates the potential for differential bias in bacterial community profiles resulting from the choice of sequencing platform alone.

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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 … (2012)

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. Copyright Â© 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Cold Spring Harb Mol Case Stud

Journal ID (iso-abbrev): Cold Spring Harb Mol Case Stud

Journal ID (hwp): cshmcs

Journal ID (pmc): cshmcs

Journal ID (publisher-id): cshmcs

Title: Cold Spring Harbor Molecular Case Studies

Publisher: Cold Spring Harbor Laboratory Press

ISSN (Electronic): 2373-2873

Publication date (Print): November 2016

Volume: 2

Issue: 6

Electronic Location Identifier: a001073

Affiliations

[1 ]Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;

[2 ]Genetic Counseling Graduate Program, Long Island University (LIU), Brookville, New York 11548, USA;

[3 ]Utah Foundation for Biomedical Research, Salt Lake City, Utah 84107, USA;

[4 ]Affiliated Genetics, Salt Lake City, Utah 84109, USA;

[5 ]Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-5618, USA;

[6 ]Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90089, USA;

[7 ]Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA

Author notes

[8]

These authors contributed equally to this work.

Corresponding author: gholsonjlyon@ 123456gmail.com

Article

Publisher ID: MalcolmsonMCS001073

DOI: 10.1101/mcs.a001073

PMC ID: 5111007

SO-VID: 4ecff8a4-026e-4860-87f5-84609e24ed0c

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted reuse and redistribution provided that the original author and source are credited.

History

Date received : 21 March 2016

Date accepted : 13 July 2016

Page count

Pages: 13

Funding

Funded by: National Institutes of Health (NIH) http://dx.doi.org/10.13039/100000002

Award ID: HG006465

Funded by: NIH http://dx.doi.org/10.13039/100000002

Award ID: R01 NS34509

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SCN8A mutation in a child presenting with seizures and developmental delays

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Abstract

Most cited references 19

Gene: a gene-centered information resource at NCBI

Performance comparison of Illumina and ion torrent next-generation sequencing platforms for 16S rRNA-based bacterial community profiling.

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

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Cited by 6

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