title: Deep intronic APC mutations explain a substantial proportion of patients with familial or early-onset adenomatous polyposis.
abstract: To uncover pathogenic deep intronic variants in patients with colorectal adenomatous polyposis, in whom no germline mutation in the APC or MUTYH genes can be identified by routine diagnostics, we performed a systematic APC messenger RNA analysis in 125 unrelated mutation-negative cases. Overall, we identified aberrant transcripts in 8% of the patients (familial cases 30%; early-onset manifestation 21%). In eight of them, two different out-of-frame pseudoexons were found consisting of a 167-bp insertion from intron 4 in five families with a shared founder haplotype and a 83-bp insertion from intron 10 in three patients. The pseudoexon formation was caused by three different heterozygous germline mutations, which are supposed to activate cryptic splice sites. In conclusion, a few deep intronic mutations contribute substantially to the APC mutation spectrum. Complementary DNA analysis and/or target sequencing of intronic regions should be considered as an additional mutation discovery approach in polyposis patients.
authors.affiliation: Institute of Human Genetics, University of Bonn, Sigmund-Freud-Strasse 25,Bonn, Germany. isabel.spier@uni-bonn.de
authors.forename: Isabel
authors.initials: I
authors.lastname: Spier
authors.forename: Sukanya
authors.initials: S
authors.lastname: Horpaopan
authors.forename: Stefanie
authors.initials: S
authors.lastname: Vogt
authors.forename: Siegfried
authors.initials: S
authors.lastname: Uhlhaas
authors.forename: Monika
authors.initials: M
authors.lastname: Morak
authors.forename: Dietlinde
authors.initials: D
authors.lastname: Stienen
authors.forename: Markus
authors.initials: M
authors.lastname: Draaken
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D009154:Mutation
chemical_list: D025601:Adenomatous Polyposis Coli Protein