Analysis of rare APC variants at the mRNA level: six pathogenic mutations and literature review.

J Mol Diagn 2009 Mar 5;11(2):131-9. Epub 2009 Feb 5.

Institute of Human Genetics, Bonn, Germany.

In monogenic disorders, the functional evaluation of rare, unclassified variants helps to assess their pathogenic relevance and can improve differential diagnosis and predictive testing. We characterized six rare APC variants in patients with familial adenomatous polyposis at the mRNA level. APC variants c.531 + 5G>C and c.532-8G>A in intron 4, c.1409-2_1409delAGG in intron 10, c.1548G>A in exon 11, and a large duplication of exons 10 and 11 result in a premature stop codon attributable to aberrant transcripts whereas the variant c.1742A>G leads to the in-frame deletion of exon 13 and results in the removal of a functional motif. Mutation c.1548G>A was detected in the index patient but not in his affected father, suggesting mutational mosaicism. A literature review shows that most of the rare APC variants detected by routine diagnostics and further analyzed at the transcript level were evaluated as pathogenic. The majority of rare APC variants, particularly those located close to exon-intron boundaries, could be classified as pathogenic because of aberrant splicing. Our study shows that the characterization of rare variants at the mRNA level is crucial for the evaluation of pathogenicity and underlying mutational mechanisms, and could lead to better treatment modalities.

Download full-text PDF

Source
http://linkinghub.elsevier.com/retrieve/pii/S152515781060218
Publisher Site
http://dx.doi.org/10.2353/jmoldx.2009.080129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665862PMC
March 2009
29 Reads

Publication Analysis

Top Keywords

apc variants
20
rare apc
16
mrna level
12
literature review
8
variants mrna
8
variants
7
apc
5
rare
5
c1548g>a exon
4
intron c1548g>a
4
diagnostics analyzed
4
transcript level
4
analyzed transcript
4
routine diagnostics
4
duplication exons
4
detected routine
4
large duplication
4
c1409-2_1409delagg intron
4
exon large
4
evaluated pathogenic
4

Similar Publications