Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations
Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations
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DOI：
10.1002/acn3.50822
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发表时间：
2019-07-01
影响因子：
5.3
通讯作者：
Berkovic, Samuel F.
中科院分区：
文献类型：
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作者：
Cameron, Jillian M.;Maljevic, Snezana;Berkovic, Samuel F.
目的分析除致癫痫进行性肌阵挛变异体p.a g320his外的KCNC1变异体的临床表型，确定所鉴定的变异体对电生理功能的影响，并探讨基因型-表型-生理的相关性。方法对10例KCNC1推定致病变异进行分析。变异是通过全外显子组测序或基因面板测试确定的。分析临床表型数据。为了确定KCNC1编码的K(v)3.1通道中检测到的变异对功能的影响，我们使用了非洲爪蟾卵母细胞表达系统和自动双电极电压箝制。结果6例无亲和关系的患者均有发育性癫痫性脑病和复发性新发变异p.a ala421val （c.1262C > T）。p.Ala421Val的功能分析显示，功能丧失通过全细胞电流的显著降低，但没有显性负作用。三名患者具有无癫痫发作的发育性脑病和不同的KCNC1变体的不同表型，所有这些都导致全细胞电流减少的功能丧失。在第十种情况下对变型p.Ala513Val （c.1538C > T）的评价表明它是一个不确定意义的变型。这是首次报道由KCNC1突变引起的发展性和癫痫性脑病病例。与KCNC1相关的表型谱现在扩大到不仅包括进行性肌阵挛性癫痫，还包括婴儿期发病的发展性和癫痫性脑病，以及无癫痫发作的发展性脑病。功能丧失是一个关键特征，但这些表型的明确电生理分离尚未出现。
Objective To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy-causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype-phenotype-physiological correlations. Methods Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole-exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the K(v)3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two-electrode voltage clamping were used. Results Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole-cell current, but no dominant-negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole-cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance. Interpretation These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.