Abstract

A novel mutation at codon 441 in exon 10 of the adenomatous polyposis coli (APC) gene was identified in a South African family of mixed ancestry, using a convenient, non-radioactive, heteroduplex-SSCP screening assay. This single thymidine deletion after nucleotide position 1322 creates a frameshift resulting in a downstream stop codon at amino acid residue 453 of the APC gene. Genotypes of nine family members were subsequently correlated with the presence or absence of congenital hypertrophy of the retinal pigment epithelium (CHRPE), since expression of this common extracolonic manifestation of FAP is largely determined by the length of the truncated protein. CHRPE was absent in the five unaffected family members analysed, while four mutation positive subjects showed these ophthalmic lesions. Correlation between the molecular analysis and ophthalmic examinations, performed without knowledge of clinical and genetic status respectively, provided additional evidence in favour of the view that the range of phenotypic expression in FAP may result from different allelic manifestations of APC mutations.