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JMD 2007, Vol. 9, No. 1
Copyright © 2007 American Society for Investigative Pathology & Association for Molecular Pathology

Consultations in Molecular Diagnostics

A Complex Rearrangement in the APC Gene Uncovered by Multiplex Ligation-Dependent Probe Amplification

Constanze Pagenstecher^*, Dorothea Gadzicki, Dietlinde Stienen^*, Siegfried Uhlhaas^*, Elisabeth Mangold^*, Nils Rahner^*, Mine Arslan-Kirchner, Peter Propping^*, Waltraut Friedl^* and Stefan Aretz^*

From the Institute of Human Genetics, * University of Bonn, Bonn, Germany; and the Institutes of Cell and Molecular Pathology and Human Genetics, Hannover Medical School, Hannover, Germany

Abstract

Germline mutations in the tumor suppressor gene APC are the underlying cause of familial adenomatous polyposis, an autosomal-dominant cancer predisposition syndrome of the colorectum. Here, we describe a complex pathogenic rearrangement in the APC gene that was detected during deletion screening and transmitted throughout at least three generations. The rearrangement consists of a deletion of 604 bp in intron 4 that impairs the binding site of the reverse primer for exon 4 and of an insertion of 119 bp in exon 4 that interferes with the binding site of the multiplex ligation-dependent probe amplification (MLPA) probes for exon 4. The insertion is composed of three duplicated sequences derived from exon 4, intron 3, and intron 4, all in inverse direction. By transcript analysis, we found that the mutation results in complete skipping of exon 4 and that it leads to a frameshift. The rearrangement would not have been identified had it occurred outside the MLPA hybridization site. Our findings demonstrate that part of the pathogenic mutations remain undetected by routine methods. Moreover, MLPA and RNA analysis alone would have led to an incorrect interpretation of a genomic deletion of exon 4.

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