3个全面性癫痫伴热性惊厥附加症家系的遗传学研究

目的分析全面性癫痫伴热性惊厥附加症家系的临床表型并筛查基因突变情况。方法收集先证者及其家系成员临床资料及外周血DNA,对患儿外周血进行包含全部目前已知癫痫相关致病基因的Illumina HiSeq 2000系列高通量全基因组测序筛查,如发现可疑突变基因,再对患儿家系其他成员进行该突变基因位点验证。结果 3个家系中有9例受累者,受累者的临床表型包括3例热性惊厥(febrile seizures,FS),3例热性惊厥附加症(febrile seizures plus,FS+),2例无热全面强直阵挛发作(afebrile generalized tonic-clonic seizures,AGTCS),1例热性惊厥附加症伴儿童失神,基因筛查发现家系1先证者及受累者父亲同时有2个基因突变,SCN5A和ABCC6基因,SCN5A为第28号外显子错义突变(c.G5239A),ABCC6为10号外显子(c.1338+1G>A)的剪切位点变异。未受累者爷爷有SCN5A基因突变,受累者奶奶有ABCC6基因突变,另2个家系未发现可疑致病基因。结论本研究发现1个未报道的可疑致病基因ABCC6,未发现已经报道的致病基因突变,进一步证明GEFS+家系是多基因遗传病,遗传机制复杂,病因学有待大样本、大家系进一步研究。

Gene mutation screening in three families with generalized epilepsy with febrile seizures plus

Objective To summarize the phenotypes and identify gene mutation in families with generalized epilepsy with febrile seizures plus (GEFS+). Methods Genomic DNA was extracted from peripheral blood lymphocytes of the proband and available members in the GEFS+ families. The phenotypes of the affected members were analyzed. Illumina HiSeq 2000 series of high throughput sequencing screening for all epilepsy related genes in children. the gene locus of the mutant gene was verified by other members of the family when the suspected mutant gene was found. Results Nine members affected in three families. Their phenotypes included 3 cases of febrile seizures (FS), 3 cases of febrile seizures plus (FS+), 2 cases of afebrile generalized onic-clonic seizures (AGTCS). One case of childhood absence epilepsy with FS+. The family was found with SCN5A and ABCC6 mutations, including exon 28 mutations (c.2592G>A) of SCN5A and exon 10 Shear site variation(c.1338+1G>A) of ABCC6. The unaffected grandfather had the mutation of SCN5A gene, and the affected grandmother had the mutation of ABCC6 gene. Conclusion One unreported suspected pathogenic gene, ABCC6, is found in this study, and we did not find the gene mutation of which had been reported. GEFS+ is a polygenic hereditary disease. Genetic mechanism is complex in GEFS+ families that needs further research.