摘要目的 分析1个伴皮层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 subcortieal infarct and leucoencephalopathy,CADASIL)家系的NOTCH3基因突变,为遗传咨询和产前诊断提供分子依据.方法 收集1个临床疑诊为CADASIL家系患者的临床资料,分析其临床特征,并对先证者和家系成员以及100名健康对照者进行NOTCH3基因DNA测序,用PolyPhen-2,SIFT软件进行功能预测,以明确致病突变.结果 先证者及家系中另2例患者(Ⅱ3、Ⅲ7)均表现为中年起病,反复脑缺血性发作、认知功能损害、记忆力减退、抑郁,头颅MRI显示多灶性腔隙性脑梗死和广泛性白质疏松.DNA测序结果显示,先证者及家系中另2例患者(Ⅱ3、Ⅲ7)存在NOTCH3基因第19外显子c.3043 T＞A(p.Cys1015Ser)杂合错义突变,另1例症状前患者(Ⅳ1)也携带有NOTCH3基因第19外显子c.3043 T＞A(p.Cys1015Ser)杂合错义突变;在100名健康对照者未检测到相同突变.功能预测分析表明,c.3043 T＞A(p.Cys1015Ser)突变可能对NOTCH3编码蛋白产生重要影响.各物种中突变位点保守性分析结果显示,该位点碱基在各物种中高度保守.结论 NOTCH3基因第19外显子c.3043 T＞A(p.Cys1015Ser)错义突变为新的致病突变.

abstractsObjective To analyze potential mutations of NOTCH3 gene in a Chinese family featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy (CADASIL) in order to facilitate genetic counseling and prenatal diagnosis.Methods The proband and related family members and 100 healthy controls were recruited.The NOTCH3 gene was screened for mutations by polymerase chain reaction and direct DNA sequencing.PolyPhen-2 and SIFT software were used to predict the protein function.Results The proband and two affected individuals from the family were adult-onset,with main clinical manifestations including recurrent transient ischemic attacks and/or strokes,cognitive impairment,memory decline,and depression.MRI findings suggested multiple cerebral infarcts and severe leukoencephalopathy.A novel heterozygous missense mutation c.3043T＞A (p.Cys1015Ser) located in exon 19 of NOTCH3 gene was identified not only in the proband and two patients,but also in an asymptomatic relative from the family.The same mutation was detected in none of the 100 unrelated healthy controls.Function analysis suggested that this mutation can severely affect the functions of this protein.Multiple sequence alignment revealed that the mutation site was extremely conserved in various species.Conclusion A novel heterozygous Cys1015Ser mutations in exon 19 of the NOTCH3 gene probably underlies the CADASIL in this family.