Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia.

Neven Maksemous,Heidi G Sutherland,Robert A Smith,Lyn R Griffiths,Larisa M Haupt

doi:10.3390/biomedicines8050134

Neven Maksemous, Heidi G Sutherland + Show 3 more

Open Access

https://doi.org/10.3390/biomedicines8050134

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Journal: Biomedicines	Publication Date: May 25, 2020
Citations: 8	License type: CC BY 4.0

Affiliation: Queensland University of Technology

Abstract

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.

Highlights

Episodic ataxias are autosomal-dominant neurological disorders characterized by severe episodes of ataxia, variably associated with progressive ataxia and ictal/interictal features.Currently, there are eight recognized forms of episodic ataxia (EA1–EA8) [1], with a ninth recently suggested subtype (EA9) linked to FGF14 [2]
Using the ataxia gene-panel list comprised of 170 genes; we identified a total of 38 novel or very rare variants
whole exome sequencing (WES) was performed in 16 individuals with ataxic symptoms (Table 1), who had been referred by clinicians for Episodic Ataxia type 2 (EA2) testing, but were found to be negative for pathogenic CACNA1A mutations, in our previous study [6]

Summary

Introduction

Episodic ataxias are autosomal-dominant neurological disorders characterized by severe episodes of ataxia (discoordination), variably associated with progressive ataxia and ictal/interictal features.Currently, there are eight recognized forms of episodic ataxia (EA1–EA8) [1], with a ninth recently suggested subtype (EA9) linked to FGF14 [2]. EA1, which features persistent myokymia and usually brief ataxia episodes, is caused by mutations in the KCNA1 gene, encoding the neuronal potassium channel Kv1.1 [3]. In the last two decades a large variety of loss of function mutations in CACNA1A, which encodes the voltage-gated calcium channel alpha1a subunit (Cav2.1 ), were found in patients with Episodic Ataxia type 2 (EA2) [5]. Using a targeted generation sequencing (NGS) gene panel, including full exonic coverage of CACNA1A, we identified causal mutations in 15 of these cases (48%) [6].

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