Familial adenomatous polyposis (FAP, OMIM #175100) is an autosomal dominant precancerous condition characterised by the appearance of hundreds to thousands of colorectal adenomas that, if not detected early and removed, invariably result in colorectal cancer (CRC). In the typical phenotype, adenomas usually occur within the second decade and become symptomatic during the third decade of life.¹ In the attenuated FAP (AFAP) phenotype, the number of colorectal adenomas is <100, with a later age at diagnosis of both polyposis and CRC than in typical FAP.^2,3

FAP is caused by germline mutations in the tumour suppressor gene APC,^5,6 which encodes a protein composed of 2843 amino acids and is formed by 14 small exons, and a large exon 15 that extends over three quarters of the coding sequence. To date, more than 500 different APC germline mutations have been reported in FAP patients (see Human Gene Mutation Database and references therein). Most of the germline mutations reported so far are localised in the 5′ half of the gene and lead to premature truncation due to single base substitutions or small insertions/deletions, resulting in nonsense or frameshift mutations and rarely in splice site mutations. In a small number of cases, single base substitutions within exonic sequences predicted to result in missense or silent variants lead to aberrant splicing.^7,8 Most APC mutations are identified with conventional mutation screening methods such as heteroduplex analysis, denaturing gradient gel electrophoresis, single strand conformational analysis (SSCP), denaturing high performance liquid chromatography (DHPLC), protein truncation test (PTT), and direct DNA sequencing. Large genomic deletions cannot be detected by these methods. The mutation detection rate in FAP families ranges from 20% to 85%, depending on the patients examined and the methods used.^9–11 Large genomic deletions have been reported to account …