Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes

Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis s yndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclus ion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-R uvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MA DH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transformi ng growth-factor beta -receptor superfamily, upstream from the SMAD pathway . Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in misse nse alterations (C124R and C376Y). Almost all available component tumors fr om mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1 A region, whereas those from mutation-negative cases did not. One proband w ith CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant propo rtion of cases of JPS and might define a small subset of cases of CS/BRRS w ith specific colonic phenotype.