MUTATIONS IN DPC4 (SMAD4) CAUSE JUVENILE POLYPOSIS SYNDROME, BUT ONLYACCOUNT FOR A MINORITY OF CASES

Juvenile polyps are present in a number of Mendelian disorders, someti mes in association only with gastrointestinal cancer [juvenile polypos is syndrome (JPS)] and sometimes as part of known syndromes (Cowden, G orlin and Banayan-Zonana) in association with developmental abnormalit ies, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in same JPS families. We have ana lysed eight JPS families for linkage to DPC4. Overall, there was no ev idence for linkage to DPC4; linkage could be excluded in two of the ei ght pedigrees and was unlikely in two others. We then tested these eig ht families and a further 13 familial and sporadic JPS cases for germl ine mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis) . Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our pati ent's mutation is a missense change (R361C); somatic missense mutation s in DPC4 have been reported previously in tumours. We therefore confi rm DPC4 as a cause of JPS, but show that there is considerable remaini ng, uncharacterized genetic heterogeneity in this disease.