Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene
Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene
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DOI：
10.1111/j.1528-1167.2010.02790.x
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发表时间：
2010-12-01
期刊：
影响因子：
5.6
通讯作者：
Zamponi, Nelia
中科院分区：
文献类型：
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作者：
Guerrini, Renzo;Cellini, Elena;Zamponi, Nelia
约12%的突变阴性的Dravet综合征（DS）患者出现α 1-钠通道亚基（SCN1A）基因缺失和重复/扩增。这种基因组异常导致功能丧失，具有严重的表型，生殖不利，因此是零星发生的。遗传突变发生在大约5%的退行性椎体滑移患者中，通常是错义的；传播发生在表现发热性癫痫发作（FS）或全身性癫痫伴发热性癫痫发作+ (GEFS+)谱的轻度患儿父母。我们在一个三代临床异质家族中发现了基因内SCN1A缺失。对SCN9A（一个假定的修饰子）的序列分析排除了致病突变、变异或假定的与表型严重程度相关的疾病相关单倍型分离。家族内表型严重程度的变异性表明，SCN1A功能丧失导致的表型谱中，由发烧引起的癫痫发作是突出的，示意图综合征细分是不合适的。即使在轻度表型的个体中也应排除SCN1A缺失。
P>Deletions and duplications/amplifications of the alpha 1-sodium channel subunit (SCN1A) gene occur in about 12% of patients with Dravet syndrome (DS) who are otherwise mutation-negative. Such genomic abnormalities cause loss of function, with severe phenotypes, reproductive disadvantage and, therefore, sporadic occurrence. Inherited mutations, occurring in similar to 5% of patients with DS, are usually missense; transmission occurs from a mildly affected parent exhibiting febrile seizures (FS) or the generalized epilepsy with febrile seizures plus (GEFS+) spectrum. We identified an intragenic SCN1A deletion in a three-generation, clinically heterogeneous family. Sequence analysis of SCN9A, a putative modifier, ruled out pathogenic mutations, variants, or putative disease-associated haplotype segregating with phenotype severity. Intrafamilial variability in phenotype severity indicates that SCN1A loss of function causes a phenotypic spectrum in which seizures precipitated by fever are prominent and schematic syndrome subdivisions would be inappropriate. SCN1A deletions should be ruled out even in individuals with mild phenotypes.