Original article—alimentary tract
American Founder Mutation for Attenuated Familial Adenomatous Polyposis

https://doi.org/10.1016/j.cgh.2007.09.017Get rights and content

Background & Aims: Specific mutations in the adenomatous polyposis coli (APC) gene can lead to an attenuated form of familial adenomatous polyposis (AFAP). Although AFAP mutation carriers have a 69% risk of colorectal cancer by age 80, clinical recognition remains a challenge in some cases because they present with few colonic adenomas and are difficult to distinguish clinically from patients with sporadic polyps. Methods: Family relationships were established using family history reports, the Utah Population Database, and the public records of the Mormon Church. Genetic analysis of representative family members was performed using a 10,000 single nucleotide polymorphism array platform. Colonoscopy data were available on 120 individuals with the AFAP mutation. Results: Two large AFAP kindreds with the identical APC disease-causing mutation (c.426_427delAT) were linked to a founding couple who came to America from England around 1630. Genetic analysis showed that the 2 families share a conserved haplotype of 7.17 Mbp surrounding the mutant APC allele. The data show that 36.6% of the mutation-positive family members have fewer than 10 colonic adenomatous polyps, and 3 (6.8%) of these individuals were diagnosed with colorectal cancer. Conclusions: In view of the apparent age of this mutation, a notable fraction of both multiple-adenoma patients and perhaps even colon cancer cases in the United States could be related to this founder mutation. The colon cancer risk associated with the mutation makes genetic testing of considerable importance in patients with a personal or family history of either colonic polyps or cancer at a young age.

Section snippets

Research Subjects and Genealogy

This study was approved by the University of Utah Institutional Review Board and by the University of Utah Resource for Genetic and Epidemiologic Research, which oversees the appropriate use of the Utah Population Database. Informed consent was obtained from all research participants. Research participants included 490 members from 2 affected branches of kindred 353 (145 of these are mutation-positive) and 99 members of kindred 439 (36 of these are mutation-positive). Colonoscopy results with

Identification of Common Founder

By using family history records and standard genealogy methods, kindreds 353 and 439 were traced to a common founding couple who were born in England in the 1590s (Figure 1). The couple was married in St. Nicholas, Somerset, England, in 1615 and had 4 children born in England between 1615 and 1624. The couple, along with at least 2 of their children, arrived in America some time before 1640, when their daughter was married in Weymouth, Norfolk, Massachusetts. A son born in 1615 is the ancestor

Discussion

We previously described the clinical phenotype of 2 American kindreds with the identical APC mutation, and have long suspected common ancestry. Here we present clear evidence linking both pedigrees to a founding couple who came to America from England in the early 1600s. In addition, kindred 353 and kindred 439 members share an identical genetic haplotype of 7.17 Mbp around the APC locus. Thirteen additional American kindreds with the identical mutation share the APC haplotype. Taken together,

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    This research is supported by National Cancer Institute grants P01-CA073992 (R.W.B.) R01-CA040641 (R.W.B.), the Utah Cancer Registry, which is funded by contract number NCI-CN-67000, the Utah Department of Health, the University of Utah, and the Huntsman Cancer Foundation. Partial support of Utah Population Database is provided by the University of Utah and Huntsman Cancer Institute.

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