Screening for mutations of the APC gene in 66 Italian familial adenomatouspolyposis patients: Evidence for phenotypic differences in cases with and without identified mutation

Germline mutations in the APC gene are responsible for familial adenomatous polyposis (FAP), a dominantly inherited syndrome characterized by the deve lopment of hundreds to thousands of polyps in the colon and in the rectum o f affected individuals and by variable extracolonic manifestations (gastric and duodenal polyps, osteomas, retinal lesions, and desmoid tumors). Throu gh the combined use of single strand conformation polymorphism (SSCP) analy sis and the protein truncation test (PTT), we have screened 66 Italian FAP patients and found 29 different APC mutations in a total of 34 cases. Of th e identified mutations, 15 were nonsense, 12 were 1- to 5-bp deletions or i nsertions and two were complex rearrangements, all leading to the formation of premature stop codons. Only 10 mutations had been already previously de scribed at the germline level, confirming the high heterogeneity of the APC mutational spectrum. The mean age of diagnosis in mutation positive cases and their affected relatives was significantly lower than in cases without identified mutation (30.6 vs 39.1 years, respectively; p = 0.003). In addit ion, among patients without a family history of polyposis, all mutation pos itive cases displayed at least one of the extracolonic manifestations usual ly associated with FAP, whereas in one-half of the cases without identified mutation, none of these phenotypes was observed. Although a fraction of ap parently mutation-negative cases were likely to be due to limitations of th e mutation screening strategy our results suggest, in agreement with previo us reports, that allelic and/or genetic heterogeneity might be responsible for the phenotypic variability observed in FAP patients. Hum Mutat 13:116-1 23, 1999. (C) 1999 Wiley-Liss, Inc.