结节性硬化症一家系表型异质性分析

Analysis of phenotypic heterogeneity in a family with tuberous sclerosis complex

目的阐明结节性硬化症(tuberous sclerosis complex,TSC)一家系中患者的表型异质性特征,为准确的遗传咨询及产前诊断提供依据。方法收集结节性硬化症先证者及其家系成员临床资料,采用聚合酶链反应和DNA直接测序方法进行TSC1和TSC2突变检测,确定基因突变位点,分析基因型与表型的关系。结果该家系主要临床表现包括癫痫、皮肤改变、心脏横纹肌瘤以及TSC典型的头颅MRI改变,先证者(Ⅲ:4)及胞弟(Ⅲ:6)以癫痫及皮肤改变为主,头颅MRI呈TSC特征性改变,符合临床诊断TSC,先证者之母(Ⅱ:4)表现皮肤改变,之女(Ⅳ:1)存在心脏横纹肌瘤,之外祖父(Ⅰ:1)否认存在上述临床表现。其余家族成员(Ⅰ:2,Ⅱ:3,Ⅱ:5,Ⅱ:6,Ⅱ:7,Ⅲ:1,Ⅲ:2,Ⅲ:3,Ⅲ:5,Ⅲ:7)表型正常。遗传学特点:先证者(Ⅲ:4)发现TSC2存在c.1880A>C杂合错义改变以及c.3883+3A>G疑似剪接改变,前者导致第627号氨基酸由His变为Pro(p.His627Pro),为国际上未见报道的新突变。先证者之胞弟(Ⅲ:6)、之母(Ⅱ:4)、之女(Ⅳ:1)及之外祖父(Ⅰ:1)均发现TSC2相同位点变异,其余家族成员(Ⅰ:2,Ⅱ:1,Ⅱ:3,Ⅱ:5,Ⅲ:5)上述两位点为野生型。结论本研究阐明了一个TSC家系表型异质性特征。先证者TSC2 c.1880A>C(p.His627Pro)为新生致病性突变,c.3883+3A>G可能为新生致病性突变,扩展了TSC2的突变谱。同时,本研究结果为此家系准确的遗传咨询和进一步的产前诊断提供了依据。

Objective To elucidate the characteristics of phenotypic heterogeneity in patients with tuberous sclerosis complex（ TSC） in a family and to provide a possibility of accurate genetic counseling and prenatal diagnosis. Methods Clinical data of a tuberous sclerosis complex（ TSC） proband and his family members were collected. All coding exons of the TSC1 and TSC2 and their flanking intronic sequences were amplified by polymerase chain reaction and subjected to direct sequencing. Relationship between genotype and phenotype of five patients with TSC in a family was analyzed. Results Clinical characteristics presented as epilepsy,skin changes,cardiac rhabdomyoma and typical MRI of TSC. Both of the proband（ Ⅲ： 4） and his brother（ Ⅲ： 6） were clinically diagnosed as TSC according to their epilepsy,skin changes and typical TSC MRI manifestation,their mother（ Ⅱ： 4） only showed skin changes,while their grandfather（ Ⅰ： 1） did not have any above-mentioned clinical manifestation obviously. Proband＇s daughter（ Ⅳ： 1） had cardiac rhabdomyoma,and the remain members of the family（ Ⅰ： 2,Ⅱ： 3,Ⅱ： 5,Ⅱ： 6,Ⅱ： 7,Ⅲ： 1,Ⅲ： 2,Ⅲ： 3,Ⅲ： 5,Ⅲ： 7） all had normal phenotype.The c. 1880 A 〉C（ p. His627 Pro） and c. 3883 ＋ 3 A〉 G of TSC2 were found in proband（ Ⅲ： 4）,Ⅲ： 6,Ⅱ： 4,Ⅳ： 1 and Ⅰ： 1,and they were not reported until now. Meanwhile,wild type of the above two sites of TSC2 were found in the remain members of the family.Conclusion In one family with TSC,the patients may have characteristics of phenotypic heterogeneity. The C. 1880 A〉 C（ p.His627 Pro） of TSC2 is a novel disease-causing mutation,and may extend the mutation spectrum of TSC2,and C. 3883 ＋ 3 A〉 G might be a novel disease-causing mutation of TSC.