The SCN1A Mutation Database: Updating Information and Analysis of the Relationships among Genotype, Functional Alteration, and Phenotype
The SCN1A Mutation Database: Updating Information and Analysis of the Relationships among Genotype, Functional Alteration, and Phenotype
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SCN1A突变数据库：更新信息并分析基因型、功能改变和表型之间的关系
DOI：
10.1002/humu.22782
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发表时间：
2015-06-01
期刊：
影响因子：
3.9
通讯作者：
Liao, Wei-Ping
中科院分区：
文献类型：
--
作者：
Meng, Heng;Xu, Hai-Qing;Liao, Wei-Ping
在表型和遗传方式差异很大的癫痫患者和无症状携带者中已发现SCN1A基因突变。这给评估SCN1A突变的致病性带来了挑战。我们系统地回顾了所有的SCN1A突变，并建立了一个包含功能变化信息的数据库。总共发现了1257个突变，其中81.8%是不复发的。表型严重程度与错义突变频率呈负相关。进一步的分析表明，基因型、功能改变和表型之间存在密切关系。位于不同钠通道区域的错义突变与不同的功能变化相关。孔区错义突变的特征是完全丧失功能，类似于单倍体功能不全。具有严重表型的突变更多地位于孔区，这表明功能改变在评估致病性方面至关重要，并可应用于患者管理。表型严重程度与家族性发病呈负相关，不完全外显与错义和剪接点突变相关，而与截断或基因组重排无关，提示临床遗传咨询应用。12.5-25.0%的嵌合体突变是潜在致病的，外显率较低，这表明需要进一步研究致病程度较低的基因组变异。
Mutations in the SCN1A gene have been identified in epilepsy patients with widely variable phenotypes and modes of inheritance and in asymptomatic carriers. This raises challenges in evaluating the pathogenicity of SCN1A mutations. We systematically reviewed all SCN1A mutations and established a database containing information on functional alterations. In total, 1,257 mutations have been identified, of which 81.8% were not recurrent. There was a negative correlation between phenotype severity and missense mutation frequency. Further analyses suggested close relationships among genotype, functional alteration, and phenotype. Missense mutations located in different sodium channel regions were associated with distinct functional changes. Missense mutations in the pore region were characterized by the complete loss of function, similar to haploinsufficiency. Mutations with severe phenotypes were more frequently located in the pore region, suggesting that functional alterations are critical in evaluating pathogenicity and can be applied to patient management. A negative correlation was found between phenotype severity and familial incidence, and incomplete penetrance was associated with missense and splice site mutations, but not truncations or genomic rearrangements, suggesting clinical genetic counseling applications. Mosaic mutations with a load of 12.5-25.0% were potentially pathogenic with low penetrance, suggesting the need for future studies on less pathogenic genomic variations.