NOTCH3基因测序发现一个新的致病突变CADASIL诊断的复杂性

Sequence analysis of the NOTCH3 gene discover a novel pathogenic mutation: complexity in the diagnosis of CADASIL

目的通过一个新发现的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(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)致病基因,说明基因测序对于CADASIL诊断的必要性及CADASIL诊断的复杂性。方法对1例疑似CADASIL患者的临床表现、实验室检查、影像学检查、家系及基因测序进行分析。临床上主要表现为反复缺血性卒中及进行性记忆力下降;实验室检查排除一些高凝疾病及血管炎;头部MRI提示皮质下白质广泛对侧性信号异常及多部位的新旧梗死病灶;家系分析患者家族成员存在偏头痛、反复卒中及记忆力下降;基因测序提示NOTCH3基因3号外显子存在一个基因突变(c.331G>T p.Gly111Cys),而这个突变位点截止到目前并未报道过。结果结合患者临床表现、影像学、家系及基因测序分析确诊该患者为CADASIL,通过分析CADASIL突变基因的致病机制确认该患者存在的突变基因为CADASIL一个新发现的致病突变。结论新的CADASIL致病基因突变的发现强调了基因测序及提高对突变基因致病机制认识的重要性。

Objective To emphasis the the importance of genetic tests and the complexity in the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy（ CADASIL） by discovering a novel mutation. Methods Analyze clinical manifestation,laboratory examination,imaging examination,pedigree investigation and genetic tests of a patient suspected CADASIL. The clinical manifestation included recurrent ischemic stroke and progressive memory loss. Laboratory tests excluded hypercoagulable disorders and vasculitides. Magnetic resonance imaging（ MRI） of the patient＇s brain revealed symmetric and extensive abnormal signal in the subcortical white matter and novel or old infarction lesions. The family member of the patient had the history of migraine,recurrent stroke and memory loss. Sequence analysis of hot point mutations of the NOTCH3 gene,unveiled a novel mutation,c. 331 G T（ p. Gly111 Cys 3 exon）,which have not detected in Human Gene Mutation Database up to now. Results Combined with the characteristics of clinical manifestation,imaging of brain,family history and genetic sequence,the patient was identified as CADASIL and the novel mutation had been considered as the pathogenic mutation of CADASIL. Conclusion The fingding of the novel pathogenic gene emphasize the significance of genetic tests and the cognition in pathogenesis of mutation gene.