结节性硬化症伴癫痫发作患者基因突变类型与临床表型相关性研究

Study on the relationship between gene mutation types and clinical phenotypes in patients with tuberous sclerosis complex accompanied by epilepsy

目的探讨结节性硬化症伴癫痫发作患者的基因突变类型与临床表型的关系。方法对2013年10月至2019年10月在广东三九脑科医院确诊的结节性硬化症伴癫痫发作患者进行TSC基因检测,对基因阳性者进行基因突变类型分型,并收集其临床资料,从而探讨不同基因突变类型与临床表型的关系。结果共85例患者TSC基因检测阳性,其中TSC1基因突变34例(40.0%)分别为:剪切突变4例(11.8%)、移码突变10例(29.4%)、无义突变4例(11.8%)及错义突变16例(47.0%)。TSC2基因突变51例(60.0%)分别为:剪切突变3例(5.9%)、移码突变19例(37.3%)、无义突变1例(1.9%)、错义突变25例(49.0%)及大片段缺失3例(5.9%)。突变类型均以移码突变及错义突变的突变率较高。对起病年龄进行分层,分为≤1岁、~3岁、~6岁、~18岁、>18岁,发现不同起病年龄在TSC1及TSC2基因中有统计学差异(P<0.05)。同时发现肾脏病变及智力低下的发生率在TSC1及TSC2基因中有统计学意义(分别P<0.05)。此外,根据基因突变类型进行分组,分为移码突变组、错义突变组及其他突变(包括剪切突变、无义突变及大片段缺失)组,发现心脏病变的发生率在不同基因突变类型中有统计学差异(分别P<0.05)。结论TSC1及TSC2基因突变类型及临床表型多样,TSC2起病年龄更小,更容易出现肾脏病变及智力低下。错义突变更易发生心脏病变。基因类型-临床表型的研究可对TSC患者的疾病发展及预后做出初步评估。

Objective To explore the relationship between gene mutation types and clinical phenotypes in patients with tuberous sclerosis complex accompanied by epilepsy.Methods TSC gene was detected in patients with tuberous sclerosis accompanied by epilepsy diagnosed in Guangdong Sanjiu brain hospital from October 2013 to October 2019.The patients with gene positive were genotyped and the clinical data of the patients with gene positive were collected to explore the relationship between different gene mutation types and clinical phenotypes.Results 85 patients were TSC gene positive,of which 34(40.0%)were TSC1 gene mutation in which 4(11.8%)were splice mutation,10(29.4%)were frameshift mutation,4(11.8%)were nonsense mutation and 16(47.0%)were missense mutation.51(60.0%)were TSC2 gene mutation,in which 3 were splice mutation(5.9%),19 were frameshift mutation(37.3%),1 was nonsense mutation(1.9%),25 were missense mutation(49.0%)as well as 3 were large fragment deletion(5.9%).The mutation rate of frameshift mutation and missense mutation was higher.The age of onset was divided into≤1 year old,~3 years old,~6 years old,~18 years old and>18 years old.It was found that there were significant differences in TSC1 and TSC2 genes among different age of onset(P<0.05).At the same time,the incidence of renal disease and mental retardation was statistically significant in TSC1 and TSC2 genes(P<0.05 respectively).In addition,according to the type of gene mutation,the patients were divided into three groups:frameshift mutation group,missense mutation group and other mutations(including splice mutation,nonsense mutation and large fragment deletion)group.It was found that the incidence of heart disease was significantly different in different gene mutation types(P<0.05 respectively).Conclusion There were many different types of TSC1 and TSC2 gene mutation types and clinical phenotypes.The onset age of TSC2 mutation is younger and more prone to have kidney disease and mental retardation.Missense mutations are more likely to develop heart disease.The study of genotype-phenotype relationship can make a preliminary assessment of disease development and prognosis in TSC patients.