Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures
Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures
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伴有热性惊厥的家族性部分性癫痫的马赛克 SCN1A 突变
DOI：
10.1111/j.1601-183x.2011.00756.x
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发表时间：
2012-03-01
影响因子：
2.5
通讯作者：
Liao, W. -P.
中科院分区：
文献类型：
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作者：
Shi, Y. -W.;Yu, M. -J.;Liao, W. -P.
SCN 1A是最相关的癫痫基因。SCN 1A的突变产生的表型从极其严重的Dravet综合征（DS）到轻度的全身性癫痫伴热性惊厥（GEFS+）。在罕见的家族性DS中发现了嵌合性SCN 1A突变。推测SCN 1A嵌合突变可能导致临床上更常见的其他类型的家族性癫痫伴热性惊厥（FS）。因此，我们使用变性高效液相色谱和测序技术在13个部分性癫痫伴前驱热性惊厥（PEFS+）家族中筛查了SCN 1A突变。通过焦磷酸测序进一步定量镶嵌现象的水平。在2个不相关的PEFS+家系中发现了2个嵌合起源的SCN 1A错义突变，占所检测的PEFS+家系的15.4%（2/13）。其中1例c.5768A>G/p.Q1923R突变率为25.0%的嵌合体携带者发生了单纯FS，另1例c.4847T>C/p.I1616T突变率为12.5%的嵌合体携带者无症状。他们的杂合子子女有PEFS+。复发性传播发生在两个家庭中，如以前报道的大多数生殖系嵌合的家庭所指出的。本研究中发现的两种嵌合突变与大多数先前研究中发现的更具破坏性的截短和剪接位点突变相比，破坏性较小。这是第一次报告嵌合SCN 1A突变的家庭先证者不表现出DS，但表现出一个温和的表型。因此，在遗传咨询时应谨慎接触这些轻度病例的家庭，并应排除与高复发风险相关的镶嵌起源的可能性。
SCN1A is the most relevant epilepsy gene. Mutations of SCN1A generate phenotypes ranging from the extremely severe form of Dravet syndrome (DS) to a mild form of generalized epilepsy with febrile seizures plus (GEFS+). Mosaic SCN1A mutations have been identified in rare familial DS. It is suspected that mosaic mutations of SCN1A may cause other types of familial epilepsies with febrile seizures (FS), which are more common clinically. Thus, we screened SCN1A mutations in 13 families with partial epilepsy with antecedent febrile seizures (PEFS+) using denaturing high‐performance liquid chromatography and sequencing. The level of mosaicism was further quantified by pyrosequencing. Two missense SCN1A mutations with mosaic origin were identified in two unrelated families, accounting for 15.4% (2/13) of the PEFS+ families tested. One of the mosaic carriers with ∼25.0% mutation of c.5768A>G/p.Q1923R had experienced simple FS; another with ∼12.5% mutation of c.4847T>C/p.I1616T was asymptomatic. Their heterozygous children had PEFS+. Recurrent transmission occurred in both families, as noted in most of the families with germline mosaicism reported previously. The two mosaic mutations identified in this study are less destructive missense, compared with the more destructive truncating and splice‐site mutations identified in the majority of previous studies. This is the first report of mosaic SCN1A mutations in families with probands that do not exhibit DS, but manifest only a milder phenotype. Therefore, such families with mild cases should be approached with caution in genetic counseling and the possibility of mosaicism origin associated with high recurrence risk should be excluded.