Whole-Exome Sequencing Implicates SCN2A in Episodic Ataxia, but Multiple Ion Channel Variants May Contribute to Phenotypic Complexity.
Whole-Exome Sequencing Implicates SCN2A in Episodic Ataxia, but Multiple Ion Channel Variants May Contribute to Phenotypic Complexity.
复制标题
DOI：
10.3390/ijms19103113
复制
发表时间：
2018-10-11
影响因子：
5.6
通讯作者：
Griffiths LR
中科院分区：
文献类型：
--
作者：
Maksemous N;Smith RA;Sutherland HG;Sampaio H;Griffiths LR
尽管基于靶向基因测序的诊断的临床应用很有价值，但全外显子组测序也已成为全球分子遗传学实验室的成功诊断工具。 2 型阵发性共济失调 (EA2) 的分子遗传学检测通常仅针对已知会导致 EA2 的特定钙通道基因 (CACNA1A)。在 CACNA1A 基因中未发现突变的情况下，确定致病基因非常重要，以便可以优先为患者提供更有效的治疗。在这里，我们介绍了一个先证者的病例，该先证者患有复杂的发作性共济失调 (EA)/癫痫表型，其父亲患有 EA；以及一位未受影响的母亲，其 CACNA1A 基因突变均为阴性。通过全外显子组测序对这三者进行了研究，以确定导致复杂的 EA/癫痫表型的候选基因。钠通道α2亚基的三种罕见或新颖的变体； SCN2A (c.3973G>T: p.Val1325Phe)，钾通道，Kv3.2； KCNC2 (c.1006T>C: p.Ser336Pro) 和钠通道 Nav1.6；在先证者中发现了 SCN8A (c.3421C>A: p.Pro1141Thr) 基因。虽然 SCN2A 变异可能是阵发性共济失调的原因，但每种变异都可能有助于该家族中观察到的表型。这项研究强调，使用全外显子组/基因组测序的一个主要挑战是识别与复杂疾病相关的独特致病突变。
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.
登录
查看更多内容
影响因子：
3.4
作者：
Wagnon JL;Meisler MH
通讯作者：
Meisler MH
影响因子：
64.5
作者：
Klassen T;Davis C;Goldman A;Burgess D;Chen T;Wheeler D;McPherson J;Bourquin T;Lewis L;Villasana D;Morgan M;Muzny D;Gibbs R;Noebels J
通讯作者：
Noebels J
影响因子：
11.2
作者：
Gardella, Elena;Becker, Felicitas;Weber, Yvonne G.
通讯作者：
Weber, Yvonne G.
影响因子：
7
作者：
Ng, PC;Henikoff, S
通讯作者：
Henikoff, S
影响因子：
14.5
作者：
Jen, J. C.;Graves, T. D.;Baloh, R. W.
通讯作者：
Baloh, R. W.