Abstract: Objective To summarize and analyze the clinical phenotype and genetic characteristics of a family with TSC1 gene mutation in tuberous sclerosis,so as to provide evidence for genetic counseling.Methods The clinical phenotypes of 6 probands and their grandmothers,aunts,aunts,mothers and sisters in the three generations of close relatives of the family were consistent with tuberous sclerosis.The probands and their parents and sisters were amplified by PCR for all coding regions and flanking shear sites of TSC1 and TSC2 genes,and the products were sequenced for mutation analysis.At the same time,35 unrelated normal controls were detected,The correlation between the gene variation and clinical phenotype was further analyzed.Results NM was found in exon 10 of TSC1 gene in proband,mother and sister_ 000368.5:c.917_ The 923upGTGCTAC mutation resulted in abnormal protein level(the amino acid at the position of p.Ser309Cysfs * 34309 changed from serine to cysteine,and from the position of 309,continued translation 34 met the termination codon,resulting in early termination of protein translation).The father did not find the mutation,and the father's clinical phenotype was normal,and the mutation was not detected in 35 normal controls.After searching HGMD database,this mutation is a new mutation,and there has been no report of this mutation in the past,which is consistent with the genetic co-segregation of disease phenotypes in the family.Conclusion TSC1 gene c.917_ The 923 base repeat frameshift mutation may be the cause of tuberous sclerosis in this family.The clinical phenotype of TSC1 gene mutation at the same site in the same family has strong heterogeneity.

Key words: TSC1 gene, Tuberous sclerosis, Genetics

摘要： 目的 对一个TSC1基因突变的结节性硬化症家系临床表型及遗传学特征总结分析,为遗传咨询提供依据。方法 在该家系三代近亲中先证者及其外祖母、大姨、三姨、母亲、妹妹6人临床表型符合结节性硬化症,并对先证者及其父母、妹妹进行TSC1、TSC2基因全部编码区及侧翼剪切位点进行PCR扩增,产物进行测序进行突变分析,同时对35名无亲缘关系的正常对照进行检测,进一步分析该基因变异与临床表型相关性。结果 先证者及其母亲、妹妹均在TSC1基因第10号外显子存在NM_000368.5:c.917_923dupGTGCTAC突变,导致蛋白水平发生异常(p.Ser309Cysfs*34,309位置的氨基酸由丝氨酸变为半胱氨酸,从309这个位置开始,继续翻译34遇到终止密码子,导致了蛋白翻译提前终止),父亲未发现该变异,且父亲临床表型正常,35名正常对照中未检测到突变。经检索HGMD数据库该突变为新发突变,既往未见该突变相关报道,符合家系疾病表型遗传共分离。结论 TSC1基因c.917_923碱基重复移码突变可能为该家系结节性硬化症患病的原因。同一家系中TSC1基因相同位点突变临床表型具有很强的异质性。

关键词: TSC1基因, 结节性硬化症, 遗传学