Genotype-phenotype correlations in 19 Dutch cases with APC gene deletions and a literature review

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. The genotype-phenotype correlations for these APC deletions have not been studied in detail. 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. 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. 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. Most of the deletion families (83%) displayed a classic familial adenomatous polyposis (FAP) phenotype (100-2000 adenomas). 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. 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). Methods to identify such deletions should therefore be included in routine germ line APC mutation analysis. While most total and partial APC deletions lead to a classic FAP phenotype, specific (in-frame) deletions may lead to an attenuated polyposis phenotype.