American founder mutation for attenuated familial adenomatous polyposis

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.

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.

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.

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.