Prevalence of MYH germline mutations in Swiss APC mutation‐negative polyposis patients

In 10–30% of patients with classical familial adenomatous polyposis (FAP) and up to 90% of those with attenuated (<100 colorectal adenomas; AFAP) polyposis, no pathogenic germline mutation in the adenomatous polyposis coli ( APC ) gene can be identified ( APC mutation‐negative). Recently, biallelic mutations in the base excision repair gene MYH have been shown to predispose to a multiple adenoma and carcinoma phenotype. This study aimed to ( i ) assess the MYH mutation carrier frequency among Swiss APC mutation‐negative patients and ( ii ) identify phenotypic differences between MYH mutation carriers and APC/MYH mutation‐negative polyposis patients. Seventy‐nine unrelated APC mutation‐negative Swiss patients with either classical ( n = 18) or attenuated ( n = 61) polyposis were screened for germline mutations in MYH by dHPLC and direct genomic DNA sequencing. Overall, 7 (8.9%) biallelic and 9 (11.4%) monoallelic MYH germline mutation carriers were identified. Among patients with a family history compatible with autosomal recessive inheritance ( n = 45), 1 (10.0%) out of 10 classical polyposis and 6 (17.1%) out of 35 attenuated polyposis patients carried biallelic MYH alterations, 2 of which represent novel gene variants (p.R171Q and p.R231H). Colorectal cancer was significantly ( p < 0.007) more frequent in biallelic mutation carriers (71.4%) compared with that of monoallelic and MYH mutation‐negative polyposis patients (0 and 13.8%, respectively). On the basis of our findings and earlier reports, MYH mutation screening should be considered if all of the following criteria are fulfilled: ( i ) presence of classical or attenuated polyposis coli, ( ii ) absence of a pathogenic APC mutation, and ( iii ) a family history compatible with an autosomal recessive mode of inheritance. © 2005 Wiley‐Liss, Inc.