SMAD4 and hereditary hemorrhagic telangiectasia: While loss-of-function mutations in ALK1 or ENG account for roughly 85% of all cases of HHT, approximately 5% of patients carry deleterious variants in SMAD4, which encodes an essential transcriptional effector of TGF-β signaling [32], while a handful of patients feature mutations within BMP9, which encodes the ligand for the ALK1–ENG receptor complex [33,34].