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Large intron 14 rearrangement in APC results in splice defect and attenuated FAP

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Abstract

Familial adenomatous polyposis [FAP (OMIM 175100)] is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a combination of screening and/or surgical intervention, a ~99% lifetime risk of colorectal cancer. A subset of FAP patients develop an attenuated form of the condition characterized by lower numbers of colonic polyps (highly variable, but generally less than 100) and a lower lifetime risk of colorectal cancer, on the order of 70%. We report the diagnosis of three attenuated FAP families due to a 1.4-kb deletion within intron 14 of APC, originally reported clinically as a variant of unknown significance (VUS). Sequence analysis suggests that this arose through an Alu-mediated recombination event with a locus on chromosome 6q22.1. This mutation is inherited by family members who presented with an attenuated FAP phenotype, with variable age of onset and severity. Sequence analysis of mRNA revealed an increase in the level of aberrant splicing of exon 14, resulting in the generation of an exon 13–exon 15 splice-form that is predicted to lead to a frameshift and protein truncation at codon 673. The relatively mild phenotypic presentation and the intra-familial variation are consistent with the leaky nature of exon 14 splicing in normal APC. The inferred founder of these three families may account for as yet undetected affected branches of this kindred. This and similar types of intronic mutations may account for a significant proportion of FAP cases where APC clinical analysis fails because of the current limitations of testing options.

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Abbreviations

FAP:

Familial adenomatous polyposis

APC:

Adenomatous polyposis coli

VUS:

Variant of unknown significance

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Acknowledgments

We acknowledge Tom Day for medial record data evaluation, Dholani Zarook, Ryan Turner, Brian Richardson, and Debra Ma for family history data curation and pedigree construction. This research was supported by NCI grants P01-CA073992 RWB), R01CA040641(RWB) and by the Huntsman Cancer Foundation.

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Authors and Affiliations

  1. Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Room 4156, Salt Lake City, UT, 84112-5550, USA

    Thérèse M. F. Tuohy, Michelle W. Done, Michelle S. Lewandowski, Deborah W. Neklason & Randall W. Burt

  2. Saint Luke’s Hospital of Kansas City, Missouri, USA

    Patricia M. Shires

  3. University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Devki S. Saraiya

  4. Department of Pediatrics, University of California San Diego School of Medicine, California, USA

    Sherry C. Huang

  5. Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA

    Deborah W. Neklason

  6. Department of Medicine, University of Utah, Salt Lake City, UT, USA

    Randall W. Burt

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  1. Thérèse M. F. Tuohy
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  2. Michelle W. Done
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  3. Michelle S. Lewandowski
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Correspondence to Thérèse M. F. Tuohy.

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Tuohy, T.M.F., Done, M.W., Lewandowski, M.S. et al. Large intron 14 rearrangement in APC results in splice defect and attenuated FAP. Hum Genet 127, 359–369 (2010). https://doi.org/10.1007/s00439-009-0776-9

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  • DOI: https://doi.org/10.1007/s00439-009-0776-9

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