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Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia

Genomics Research Centre, Institute of Health and Biomedical Innovation (IHBI), School of Biomedical Sciences, Q Block, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove Campus, Brisbane, Queensland 4059, Australia
Author to whom correspondence should be addressed.
Biomedicines 2020, 8(5), 134;
Received: 4 May 2020 / Revised: 21 May 2020 / Accepted: 21 May 2020 / Published: 25 May 2020
Episodic Ataxias (EAs) are a small group (EA1–EA8) of complex neurological conditions that manifest as incidents of poor balance and coordination. Diagnostic testing cannot always find causative variants for the phenotype, however, and this along with the recently proposed EA type 9 (EA9), suggest that more EA genes are yet to be discovered. We previously identified disease-causing mutations in the CACNA1A gene in 48% (n = 15) of 31 patients with a suspected clinical diagnosis of EA2, and referred to our laboratory for CACNA1A gene testing, leaving 52% of these cases (n = 16) with no molecular diagnosis. In this study, whole exome sequencing (WES) was performed on 16 patients who tested negative for CACNA1A mutations. Tiered analysis of WES data was performed to first explore (Tier-1) the ataxia and ataxia-associated genes (n = 170) available in the literature and databases for comprehensive EA molecular genetic testing; we then investigated 353 ion channel genes (Tier-2). Known and potential causal variants were identified in n = 8/16 (50%) patients in 8 genes (SCN2A, p.Val1325Phe; ATP1A3, p.Arg756His; PEX7, p.Tyr40Ter; and KCNA1, p.Arg167Met; CLCN1, p.Gly945ArgfsX39; CACNA1E, p.Ile614Val; SCN1B, p.Cys121Trp; and SCN9A, p.Tyr1217Ter). These results suggest that mutations in these genes might cause an ataxia phenotype or that combinations of more than one mutation contribute to ataxia disorders. View Full-Text
Keywords: episodic ataxia; whole exome sequencing; acetazolamide episodic ataxia; whole exome sequencing; acetazolamide
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MDPI and ACS Style

Maksemous, N.; Sutherland, H.G.; Smith, R.A.; Haupt, L.M.; Griffiths, L.R. Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia. Biomedicines 2020, 8, 134.

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