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.
In this study exome sequencing of 19 HHT patients and relatives with unknown HHT genetic etiology is performed, to identify new HHT genetic drivers.
Variants in the INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, FOXO1 and SMAD6 genes as putative drivers in HHT are identified. The SMAD6 p.(Glu407Lys) variant in one of the families is identified; 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. Read the full article here.