Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes

Abstract

The APC gene is mutated in the germline of people from families where there is a predisposition to develop polyposis coli. Many mutations have been described but the relation between their site and the phenotypic expression of the disease remains unclear. The most commonly seen mutation occurs at codon 1309. Many other mutations have been described towards the 5' end of exon 15 of the APC gene but comparatively few have been seen towards the 3' end. Recent reports have indicated the possibility of a functional boundary with respect to severity and age of onset of disease, which lies towards the 5' end of the gene. This report describes a large family whose affected members present with a very variable phenotype ranging from an early onset and severe form to a comparatively mild later onset one. The mutation that predisposes to disease in this family is at a previously undescribed site that lies towards the 3' end of exon 15 of the APC gene, which results in a stop codon. Interestingly, the stop codon is 63 codons downstream of the mutation and therefore may affect the expression of the disease. The addition of this mutation to the growing list of mutations described in the APC gene may provide some insight into the genotype/phenotype relation of the disease thus contributing to the understanding and significance of mutations at specific sites in the APC gene.