A classic phenotype (ie 100–2000 polyps) is associated with mutations in codon 168–1250 (exons 4/5–exon 15) or codon 1400–1580 (exon 15). Genotype–phenotype relations have been reported extensively for small nucleotide alterations (point mutations). 8 Depending on clinical features and mutation detection techniques applied, germ line mutations in the APC gene are found in 30–80% of patients with polyposis 2, 9, 10 and most APC mutations occur in the 5′ half of its coding region. Exon 15 is by far the largest exon containing over three-quarters of the coding sequence. The APC gene is a relatively large gene, containing 15 exons and encoding a protein of 2843 amino acids. 4 MUTYH-associated polyposis (MAP) is found in 10–20% of polyposis patients. 3 Another inheritable form of polyposis is caused by recessive mutations of the MUTYH gene. 1, 2 In addition, extracolonic features such as fundic gland polyps (FGP), duodenal polyps, congenital hypertrophy of the retinal pigment epithelium (CHRPE) and desmoid tumors are often present, while a more attenuated form of FAP has also been described in which patients develop less than a hundred polyps at a relatively late age. ![]() 1 Mutation carriers are predisposed in the majority of cases to develop hundreds or even thousands of polyps and subsequently go on to develop colorectal cancer (CRC). While most total and partial APC deletions lead to a classic FAP phenotype, specific (in-frame) deletions may lead to an attenuated polyposis phenotype.įamilial adenomatous polyposis, FAP (MIM175100), is an autosomal dominant inherited disease caused by germ line mutations in the APC gene it affects approximately one in 13 500 people. Methods to identify such deletions should therefore be included in routine germ line APC mutation analysis. APC deletions were found in a considerable proportion of polyposis patients previously tested negative for APC or MUTYH (6%, 19/296) and represent 8% of all APC mutations found at our clinics (19/242). We saw no patients with APC deletions and a severe phenotype (ie >2000 polyps) on the contrary, two families carrying a deletion of exons 7–13 and one family with a deletion of exons 1–5 showed a distinctly attenuated FAP phenotype. Most of the deletion families (83%) displayed a classic familial adenomatous polyposis (FAP) phenotype (100–2000 adenomas). ![]() APC deletions were identified in 19 polyposis patients seven had a whole gene deletion, nine had a deletion involving two or more exons, and three had single exon deletions. ![]() We screened 296 index patients with polyposis, who previously had negative test results for APC or MUTYH mutations, for germ line APC gene deletions using Multiplex Ligation-dependent Probe Amplification. We aimed to assess the number of germ line APC deletions in Dutch polyposis patients, to describe the clinical phenotype(s), and to review the current literature. The genotype–phenotype correlations for these APC deletions have not been studied in detail. Partial and whole gene deletions represent a large proportion (4–33%) of the APC mutations found in polyposis patients, who previously had negative test results.
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