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Int J Mol Sci. 2018 Oct 11;19(10). pii: E3113. doi: 10.3390/ijms19103113.

Whole-Exome Sequencing Implicates SCN2A in Episodic Ataxia, but Multiple Ion Channel Variants May Contribute to Phenotypic Complexity.

Author information

1
Genomics Research Centre, Institute of Health and Biomedical Innovation (IHBI), School of Biomedical Sciences, Queensland University of Technology (QUT), Q Block, 60 Musk Ave, Kelvin Grove Campus, Brisbane 4059, QLD, Australia. n.maksemous@qut.edu.au.
2
Genomics Research Centre, Institute of Health and Biomedical Innovation (IHBI), School of Biomedical Sciences, Queensland University of Technology (QUT), Q Block, 60 Musk Ave, Kelvin Grove Campus, Brisbane 4059, QLD, Australia. r157.smith@qut.edu.au.
3
Genomics Research Centre, Institute of Health and Biomedical Innovation (IHBI), School of Biomedical Sciences, Queensland University of Technology (QUT), Q Block, 60 Musk Ave, Kelvin Grove Campus, Brisbane 4059, QLD, Australia. heidi.sutherland@qut.edu.au.
4
Department of Women and Children's Health, Randwick Campus, University of New South Wales, Randwick 2031, NSW, Australia. hugo.sampaio@health.nsw.gov.au.
5
Sydney Children's Hospital, Randwick 2031, NSW, Australia. hugo.sampaio@health.nsw.gov.au.
6
Genomics Research Centre, Institute of Health and Biomedical Innovation (IHBI), School of Biomedical Sciences, Queensland University of Technology (QUT), Q Block, 60 Musk Ave, Kelvin Grove Campus, Brisbane 4059, QLD, Australia. lyn.griffiths@qut.edu.au.

Abstract

Although the clinical use of targeted gene sequencing-based diagnostics is valuable, whole-exome sequencing has also emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. Molecular genetic tests for episodic ataxia type 2 (EA2) usually target only the specific calcium channel gene (CACNA1A) that is known to cause EA2. In cases where no mutations are identified in the CACNA1A gene, it is important to identify the causal gene so that more effective treatment can be prioritized for patients. Here we present a case of a proband with a complex episodic ataxias (EA)/seizure phenotype with an EA-affected father; and an unaffected mother, all negative for CACNA1A gene mutations. The trio was studied by whole-exome sequencing to identify candidate genes responsible for causing the complex EA/seizure phenotype. Three rare or novel variants in Sodium channel α2-subunit; SCN2A (c.3973G>T: p.Val1325Phe), Potassium channel, Kv3.2; KCNC2 (c.1006T>C: p.Ser336Pro) and Sodium channel Nav1.6; SCN8A (c.3421C>A: p.Pro1141Thr) genes were found in the proband. While the SCN2A variant is likely to be causal for episodic ataxia, each variant may potentially contribute to the phenotypes observed in this family. This study highlights that a major challenge of using whole-exome/genome sequencing is the identification of the unique causative mutation that is associated with complex disease.

KEYWORDS:

KCNC2; SCN2A; SCN8A; acetazolamide; episodic ataxia; whole-exome sequencing

PMID:
30314295
PMCID:
PMC6213185
DOI:
10.3390/ijms19103113
[Indexed for MEDLINE]
Free PMC Article

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