Suls Arvid, Claeys Kristl G, Goossens Dirk, Harding Boris, Van Luijk Rob, Scheers Stefaan, Deprez Liesbet, Audenaert Dominique, Van Dyck Tine, Beeckmans Sabine, Smouts Iris, Ceulemans Berten, Lagae Lieven, Buyse Gunnar, Barisic Nina, Misson Jean-Paul, Wauters Jan, Del-Favero Jurgen, De Jonghe Peter, Claes Lieve R F
Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium.
Hum Mutat. 2006 Sep;27(9):914-20. doi: 10.1002/humu.20350.
Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI.
婴儿严重肌阵挛性癫痫（SMEI）或Dravet综合征是一种罕见的癫痫综合征。在30%至70%的SMEI患者中，已鉴定出神经元电压门控钠通道α亚基基因（SCN1A）的截短突变和错义突变。大多数患者具有截短突变，预计为功能丧失等位基因。由于突变检测研究使用基于PCR的测序或构象敏感凝胶电泳（CSGE），微缺失也预计为功能丧失等位基因，很容易逃脱检测。我们选择了11例有或无其他特征的SMEI患者，这些患者经测序分析未检测到SCN1A突变。此外，所有患者在SCN1A的任何单核苷酸多态性（SNP）中均非杂合子，这表明他们要么对所有SNP均为纯合子，要么由于该基因的微缺失而半合子。随后，我们使用一种名为多重扩增子定量（MAQ）的定量PCR方法分析这些患者SCN1A中微缺失的存在情况，观察到3例患者缺失一个SCN1A基因拷贝。所有三个微缺失均通过荧光原位杂交（FISH）得到证实。这些发现表明，相当比例的有或无其他特征的SCN1A突变阴性SMEI患者携带包含SCN1A基因的染色体微缺失，并且SCN1A基因的单倍剂量不足是SMEI的一个病因。
