一个结节性硬化症家系的临床表现及遗传学分析

Clinical characteristics and genetic analysis of a Chinese pedigree affected with tuberous sclerosis complex

目的明确1例临床诊断为结节性硬化症(tuberous sclerosis complex,TSC)患者的致病基因,为临床诊断及遗传咨询提供依据。方法应用高通量测序分析先证者TSC1与TSC2的外显子区域,确定候选致病位点,应用Sanger测序对患者及家系成员的候选位点进行验证,依据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)指南,对位点致病性进行判定。结果先证者的TSC2(NM_000548.5)存在c.52delC(p.Leu18CysfsTer28)杂合变异,为移码变异,该位点在公共数据库均未见频率报道;Mutation Taster软件预测该变异为有害变异;先证者父母均未发现该变异,依据ACMG指南,该变异为疑似致病性变异(PVS1+PM2)。结论TSC2基因c.52delC变异为为该患者致病的原因,本研究结果丰富了TSC患者TSC2的变异谱,为该家系产前诊断和遗传咨询提供理论依据。

Objective To explore the genetic basis for a Chinese pedigree affected with tuberous sclerosis complex(TSC).Methods The TSC1 and TSC2 genes were sequenced.Candidate variant was verified by Sanger sequencing of the proband and her family members.Pathogenicity of the variant was predicted based on the American College of Medical Genetics and Genomics(ACMG)guidelines.Results The proband was found to harbor a heterozygous c.52delC frameshift variant of the TSC2 gene,which may result in synthesis of amino acid chain starting from the 18th amino acid Leu and terminating at the 28th amino acid(p.Leu18CysfsTer28).The variant was unreported in the public database.Mutation Taster software predicted that the variant is harmful.Both parents of the proband were of the wild type,suggesting that the variant has occurred de novo.Based on the ACMG guidelines,the variant was predicted to be likely pathogenic(PVS1+PM2).Conclusion A novel pathogenic variant of the TSC2 gene c.52delC(p.Leu18CysfsTer28)was identified,which has enriched the mutational spectrum of TSC2 and provided a basis for genetic counseling for this pedigree.