Genetic Variants Associated with Episodic Ataxia in Korea.
Genetic Variants Associated with Episodic Ataxia in Korea.
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DOI：
10.1038/s41598-017-14254-7
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发表时间：
2017-10-23
影响因子：
4.6
通讯作者：
Choi JH
中科院分区：
文献类型：
--
作者：
Choi KD;Kim JS;Kim HJ;Jung I;Jeong SH;Lee SH;Kim DU;Kim SH;Choi SY;Shin JH;Kim DS;Park KP;Kim HS;Choi JH
发作性共济失调是一种罕见的神经系统疾病，其特征是躯干共济失调和不协调的反复发作。有五个基因（KCNA1，CACNA1A，CACNB4，SLC1A3和UBR 4）与EA相关。尽管广泛的努力遗传诊断EA，许多患者仍然未确诊。在39名韩国EA患者中进行全外显子组测序，以确定5个已知EA基因的致病性突变。我们还评估了40个导致EA作为次要表型或小脑共济失调的候选基因。18例患者（46%）揭示了可用于建立EA分子诊断的遗传信息。在11例患者中，在3个EA基因中检测到16个致病性突变。其中包括CACNA1A中的9个突变，SLC1A3中的3个突变和UBR 4中的4个突变。3例患者有两个基因突变，要么CACNA1A和SLC1A3或CACNA1A和UBR 4，表明SLC1A3和UBR 4可能作为遗传修饰剂的协同作用，对CACNA1A突变引起的异常突触前活动。在7例EA基因筛查结果阴性的患者中，在候选基因ATP 1A2、SCN 1A、TTBK 2、TGM6、FGF 14和KCND3中鉴定出潜在的致病突变。本研究证实了韩国EA的遗传异质性，并表明全外显子组测序可能有助于EA的分子遗传学诊断。
Episodic ataxia (EA) is a rare neurological condition characterized by recurrent spells of truncal ataxia and incoordination. Five genes (KCNA1, CACNA1A, CACNB4, SLC1A3, and UBR4) have been linked to EA. Despite extensive efforts to genetically diagnose EA, many patients remain still undiagnosed. Whole-exome sequencing was carried out in 39 Korean patients with EA to identify pathogenic mutations of the five known EA genes. We also evaluated 40 candidate genes that cause EA as a secondary phenotype or cerebellar ataxia. Eighteen patients (46%) revealed genetic information useful for establishing a molecular diagnosis of EA. In 11 patients, 16 pathogenic mutations were detected in three EA genes. These included nine mutations in CACNA1A, three in SLC1A3, and four in UBR4. Three patients had mutations in two genes, either CACNA1A and SLC1A3 or CACNA1A and UBR4, suggesting that SLC1A3 and UBR4 may act as genetic modifiers with synergic effects on the abnormal presynaptic activity caused by CACNA1A mutations. In seven patients with negative results for screening of EA genes, potential pathogenic mutations were identified in the candidate genes ATP1A2, SCN1A, TTBK2, TGM6, FGF14, and KCND3. This study demonstrates the genetic heterogeneity of Korean EA, and indicates that whole-exome sequencing may be useful for molecular genetic diagnosis of EA.
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