HHT Unit, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain; Internal Medicine Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain; Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Endothelial Pathobiology and Microenvironment Group, Josep Carreras Leukaemia Research Institute, Badalona, Spain.
Eur J Intern Med. 2024 Jan;119:99-108. doi: 10.1016/j.ejim.2023.08.024. Epub 2023 Sep 9.
Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in around 90% of the patients; also 2% of patients harbor pathogenic variants at SMAD4 and GDF2. Importantly, the genetic cause of 8% of patients with clinical HHT remains unknown. Here, we present new putative genetic drivers of HHT.
To identify new HHT genetic drivers, we performed exome sequencing of 19 HHT patients and relatives with unknown HHT genetic etiology. We applied a multistep filtration strategy to catalog deleterious variants and prioritize gene candidates based on their known relevance in endothelial cell biology. Additionally, we performed in vitro validation of one of the identified variants.
We identified variants in the INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, FOXO1 and SMAD6 genes as putative drivers in HHT. We have identified the SMAD6 p.(Glu407Lys) variant in one of the families; this is a loss-of-function variant leading to the activation of the BMP/TGFβ signaling in endothelial cells.
Variants in these genes should be considered for genetic testing in patients with HHT phenotype and negative for ACVRL1/ENG mutations.
遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传的罕见血管疾病。大约 90%的患者中可检测到内皮糖蛋白（ENG）和激活素 A 受体型 II 样 1（ACVRL1）基因的致病变异；也有 2%的患者携带 SMAD4 和 GDF2 的致病性变异。重要的是，8%有临床 HHT 表现的患者的遗传病因仍然未知。在这里，我们提出了 HHT 的新潜在遗传驱动因素。
为了鉴定新的 HHT 遗传驱动因素，我们对 19 名 HHT 患者及其亲属进行了外显子组测序，这些患者和亲属的 HHT 遗传病因未知。我们应用了一种多步骤筛选策略，对有害变异进行分类，并根据其在血管内皮细胞生物学中的已知相关性对候选基因进行优先级排序。此外，我们还对鉴定出的一个变体进行了体外验证。
我们发现 INHA、HIF1A、JAK2、DNM2、POSTN、ANGPTL4、FOXO1 和 SMAD6 基因中的变体可能是 HHT 的驱动因素。我们在一个家族中发现了 SMAD6 p.(Glu407Lys) 变体；这是一种导致 BMP/TGFβ 信号在血管内皮细胞中激活的功能丧失性变异。
对于表现出 HHT 表型且 ACVRL1/ENG 突变阴性的患者，应考虑对这些基因的变异进行基因检测。
