HHT patients with SMAD4 mutation typically have an overlap syndrome with Juvenile Polyposis (JP), with patients developing both JP and HHT phenotypes [35, 36], with risk of early-onset gastrointestinal cancer and associated mortality [37, 38] In other words, the JP-associated risk of colorectal cancer in patients with SMAD4 mutation may explain the observed mortality association with SMAD4 in this study. Here, SMAD4 is linked to colorectal cancer.