The SMAD4 gene is associated with juvenile polyposis syndrome (JPS) which increase risks for gastrointestinal polyps, colorectal cancer, and gastric cancer. In some individuals, people develop both JPS and hereditary hemorrhagic telangiectasia (JPS-HHT) syndrome, a condition that causes arteriovenous (arteries and veins) malformations in organs such as the lungs, liver, or brain. Management generally includes regular endoscopic surveillance, polyp removal, and monitoring or treatment of HHT-related vascular findings in coordination with specialists experienced in these conditions. SMAD4-related conditions are not known to be more common in the Ashkenazi Jewish population.
Pathogenic variants in SMAD4 exhibit autosomal dominant inheritance. This means there is a 50% chance the condition can be passed from generation-to-generation. First degree relatives (parents, siblings, children) have a 50% chance to have the same pathogenic variant whereas second degree relatives (grandparents, aunts/uncles, nieces/nephews, half-siblings) have a 25% chance. More distant relatives have lower chances of having the same pathogenic variant when one is identified in the family.
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Written December 2025
