遗传性出血性毛细血管扩张症(HHT),也被称为Rendu-Osler综合征,是一组以常染色体显性为特征的罕见遗传疾病,多系统血管发育不良,和年龄相关的外显率。这包括皮肤动静脉畸形(AVM),大脑,肺,肝脏,和粘膜。HHT的表型和基因型之间的相关性尚不清楚。招募了HHT中国血统。全外显子组测序(WES)分析,桑格验证,并进行了共隔离。进行蛋白质印迹以监测ENG/VEGFRα信号传导。因此,胡说八道,ENG/CD105的杂合变体:c.G1169A:p.确定了患有遗传性出血性毛细血管扩张症1型(HHT1)的先证者的Trp390Ter,在M666谱系中与该疾病分离。西方印迹发现,与非携带者家庭成员相关的正常水平相比,先证者中的ENG蛋白水平下降了大约一半(下降了47.4%),而VEGFα蛋白的水平,在先证者中,下降了大约四分之一(下降25.6%),暗示ENG单倍性不足,显示在此变体的载体中,可能影响VEGFα表达下调。Pearson和Spearman相关分析进一步支持TGFβ/ENG/VEGFα信号传导,暗示血管中的ENG调节。因此,包括WES在内的下一代测序应该为基因诊断提供准确的策略,治疗,遗传咨询,以及包括HHT1患者在内的罕见遗传病的临床管理。
Hereditary hemorrhagic telangiectasia (HHT), also called Rendu-Osler syndrome, is a group of rare genetic diseases characterized by autosomal dominance, multisystemic vascular dysplasia, and age-related penetrance. This includes arteriovenous malformations (AVMs) in the skin, brain, lung, liver, and mucous membranes. The correlations between the phenotype and genotype for HHT are not clear. An HHT Chinese pedigree was recruited. Whole exome sequencing (WES) analysis, Sanger verification, and co-segregation were conducted. Western blotting was performed for monitoring ENG/VEGFα signaling. As a result, a nonsense, heterozygous variant for ENG/CD105: c.G1169A:p. Trp390Ter of the proband with hereditary hemorrhagic telangiectasia type 1 (HHT1) was identified, which co-segregated with the disease in the M666 pedigree. Western blotting found that, compared with the normal levels associated with non-carrier family members, the ENG protein levels in the proband showed approximately a one-half decrease (47.4% decrease), while levels of the VEGFα protein, in the proband, showed approximately a one-quarter decrease (25.6% decrease), implying that ENG haploinsufficiency, displayed in the carrier of this variant, may affect VEGFα expression downregulation. Pearson and Spearman correlation analyses further supported TGFβ/ENG/VEGFα signaling, implying ENG regulation in the blood vessels. Thus, next-generation sequencing including WES should provide an accurate strategy for gene diagnosis, therapy, genetic counseling, and clinical management for rare genetic diseases including that in HHT1 patients.