PURPOSE: Familial adenomatous polyposis is a phenotypically heterogeneous 
disease predisposing to colorectal cancer. It is dominantly transmitted, when 
associated with the APC gene, and recessively inherited, when associated with 
MUTYH gene. We searched for APC and MUTYH germline alterations in Italian and 
Greek patients with attenuated polyposis, a phenotypic variant whose genetic 
cause remains unknown in many cases.
METHODS: We studied 26 unrelated patients (and 16 relatives) with multiple 
colorectal adenomas (3-100, by endoscopic analysis) that had screened APC 
mutation-negative by protein truncation test. We searched for APC rearrangements 
by multiplex ligation-dependent probe amplification and for MUTYH mutations by 
sequencing. We performed a screening of five MUTYH recurrent pathogenic 
mutations in 501 Italian and 144 Greek controls.
RESULTS: One patient proved to carry an APC whole-gene deletion; 4 of 25 (16%) 
patients showed biallelic and 3 of 25 (12%) monoallelic MUTYH mutations. In the 
three heterozygous subjects no pathogenetic variants were found in OGG1, MTH1, 
APE1, MSH2, and MSH6 genes. Frequency assessment of MUTYH mutations in healthy 
subjects showed that only Y165C and G382D reach a subpolymorphic frequency.
CONCLUSION: Attenuated polyposis patients without "conventional" APC mutations 
are genetically heterogeneous, and the phenotype is not directly related to the 
germline defect. Therefore, the families' appropriate management requires an 
accurate genetic and clinical investigation.