良性家族性婴儿癫痫的致病基因谱研究

Study of Pathogenic gene spectrum in benign familial infantile epilepsy

目的探讨我国良性家族性婴儿癫痫（BFIE）家系的致病基因谱。 方法收集2006年10月至2017年6月在北京大学第一医院等4家医院就诊的BFIE家系临床资料和外周血DNA，首先采用Sanger测序方法筛查PRRT2基因突变，对于未发现PRRT2基因突变的家系再采用靶向捕获二代测序癫痫基因检测包对其候选致病基因进行突变筛查。 结果共收集71个BFIE家系（包括227例受累者），其中52个家系发现基因突变（52/71，73.2%）。43个家系为PRRT2基因突变（43/71，60.6%），移码突变见于40个家系（热点突变c.649_650insC和c.649delC分别见于29个家系和6个家系），无义突变、终止密码子突变和基因片段缺失各见于1个家系，c.560_561insT和c.679C〉T为未报道的新突变；5个家系为SCN2A基因错义突变（c.668G〉A、c．752T〉C、c.1307T〉C、c.4835C〉G和c.1737C〉G），其中c.752T〉C、c.1307T〉C、c.4835C〉G和c.1737C〉G为未报道的新突变；3个家系为KCNQ2基因错义突变（c.775G〉A、c.237T〉G和c.1510C〉T），其中c.237T〉G和c.1510C〉T为未报道的新突变；1个家系携带未报道的GABRA6基因突变（c.523G〉T）。在71个BFIE家系中，有16个家系出现阵发性运动诱发的运动障碍（PKD）受累者，进一步诊断为婴儿惊厥伴阵发性舞蹈手足徐动症（ICCA）家系，其中15个ICCA家系发现PRRT2基因突变（15/16，93.8%），余ICCA家系未发现致病基因。 结论BFIE家系基因突变检出率高，致病基因包括PRRT2、SCN2A和KCNQ2基因，其中PRRT2是BFIE的主要致病基因。GABRA6可能是BFIE新的致病基因。

ObjectiveTo investigate the gene mutations in benign familial infantile epilepsy（BFIE） in China. MethodsData of all BFIE probands and their family members were collected from Peking University First Hospital and other three hospitals between October 2006 and June 2017.Clinical phenotypes of affected members were analyzed.Genomic DNA was extracted from peripheral blood samples with standard protocol.Mutations in PRRT2 were screened using Sanger sequencing.For families that PRRT2 mutations were not detected by Sanger sequencing, candidate gene mutations were further screened by next-generation sequencing. ResultsA total of 71 families including 227 affected members were collected.Genetic testing led to the identification of gene mutations in 52 families （52/71, 73.2%）. Forty-three families had PRRT2 mutations （43/71, 60.6%）, including 40 families with frameshift mutations（hotspot mutations c. 649_650insC and c. 649delC were detected in 29 families and 6 families, respectively）, one family with nonsense mutation, one family with a loss of a stop codon, and one family with a microdeletion of the gene.C.560_561insT and c. 679C〉T were novel PRRT2 mutations.Five families had SCN2A mutations.All SCN2A mutations were missense mutations（c.668G〉A, c.752T〉C, c.1307T〉C, c.4835C〉G, c.1737C〉G）. Mutation c. 752T〉C, c.1307T〉C, c.4835C〉G, and c. 1737C〉G were novel mutations.Three families had KCNQ2 mutations.All KCNQ2 mutations were missense mutations（c.775G〉A, c.237T〉G, c.1510C〉T）. Mutation c. 237T〉G and c. 1510C〉T were novel mutations.One family had a novel GABRA6 mutation c. 523G〉T.In 71 BFIE families, 16 families had members who showed paroxysmal kinesigenic dyskinesias（PKD）and subclassified as infantile convulsions with paroxysmal choreoathetosis syndrome（ICCA）. Fifteen ICCA families were found having PRRT2 mutations （15/16, 93.8%）. The remaining ICCA family was not detected with any pathogenic mutation. ConclusionThere is high frequency of gene mutations in BFIE families.Mutations in KCNQ2, SCN2A, and PRRT2 are genetic causes of BFIE.PRRT2 is the main gene responsible for BFIE.GABRA6 mutation might be a new cause of BFIE.