伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病一家系中NOTCH3基因的新突变

Mutation of NOTCH3 gene in one family of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

目的:探讨伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(CADASIL)基因的新突变。方法:对一CADASIL先证者的家系信息进行调查和分析。对先证者进行皮肤组织活检。应用高通量测序的方法对2例患者及先证者子女进行突变基因检测。结果:电镜下,皮肤组织小动脉管壁平滑肌细胞膜和膜外基质间可见多个嗜锇颗粒沉积。家系中现存2例患者及先证者子女NOTCH3基因第6号外显子区存在一处杂合突变(c. 811T>C),导致相应氨基酸发生改变(半胱氨酸>精氨酸),迄今为止,HGMDpro数据库未见此类突变。结论:NOTCH3基因第6号外显子的杂合错义突变(c. 811T> C)为新的突变类型,是CADASIL的致病突变。

Aim: To analyze mutation of NOTCH3 gene in one Chinese family of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy( CADASIL) and the possible pathogenesis. Methods: The family information of one CADASIL family was collected and analyzed. Skin biopsy of the proband was performed. To detect mutant gene,target region capture and high-throughput sequencing were used,and interpreted the data viariation according to the guidelines of the American College of Medical Genetics and Genomics( ACMG). Results: Under electron microscopy,osmiophilic granules deposited between smooth muscle cell membrane and extramembranous matrix of arteriole wall in skin tissue were found. The gene test of the offsprings of the proband and 2 patients with CADASIL in this family showed that a heterozygous mutation was found in the exon 6 region of NOTCH3 gene( c. 811 T > C),which caused the change of corresponding amino acid( cysteine > arginine). Up to now,this mutation has never been reported by HGMDpro database. Conclusion: The heterozygous missense mutation( c. 811 T > C) in exon 6 of NOTCH3 gene is a new mutation type,which is the pathogenic mutation of CADASIL.