A novel APC mutation identified in a large Chinese family with familial adenomatous polyposis and a brief literature review

Abstract

Familial adenomatous polyposis (FAP), an autosomal dominant disease, is a colon cancer predisposition syndrome that manifests as a large number of adenomatous polyps. Mutations in the Adenomatous polyposis coli (APC) gene are responsible for the majority of cases of FAP. The purpose of the present study was to report the clinical features of a Chinese family with FAP and screen for novel mutations using the targeted next‑generation sequencing technology. Among the 29 family members, 12 were diagnosed of FAP. Based on an established filtering strategy and data analyses, along with confirmation by Sanger sequencing and co‑segregation, a novel frameshift mutation c.1317delA (p.Ala440LeufsTer14) in exon 10 of the APC gene was identified. To the best of our knowledge, this mutation has not been reported prior to the present study. In addition, it was correlated with extra‑colonic phenotypes featuring duodenal polyposis and sebaceous cysts in this family. This novel frameshift mutation causing FAP not only expands the germline mutation spectrum of the APC gene in the Chinese population, but it also increases the understanding of the phenotypic and genotypic correlations of FAP, and may potentially lead to improved genetic counseling and specific treatment for families with FAP in the future.

Figure 1.

Pedigree of the FAP family. A four-generation family composed of 29 members from Sichuan, China, was recruited in the present study. The black arrow denotes the proband, solid symbols indicate affected individuals, and open symbols indicate unaffected individuals. In total, 12 family members were diagnosed with FAP. The disease exhibited a pattern of autosomal dominant inheritance. FAP, familial adenomatous polyposis; squares, males; circles, females; symbols with diagonal lines, deceased.

Figure 2.

Clinical characterization of the proband of this pedigree. (A) Two grape beaded polyps (red arrows) and some small polyps in the transverse colon. (B) A grape beaded polyp and some small polyps (red arrows) in the transverse colon.

Figure 3.

Novel mutation in the APC gene in this pedigree. (A) The novel heterozygous mutation c.1317delA (p.Ala440LysfsTer14) was validated using Sanger sequencing. (B) Multiple sequence alignment of APC proteins from various species. Red shades showed the premature termination of amino acids, which was resulted from the deletion. This region is highly conserved acrossdifferent species. APC, Adenomatous polyposis coli.

Figure 4.

Structure modeling of the functional domains of APC protein. (A) Structure of the APC protein, the red box denotes the site of the novel mutation, the green box shows the premature termination codon, the box with a dashed blue line indicates the truncated region of this protein, and the colored squares indicate the sub-domains in the APC protein. (B) Structure modeling of wild type and p.Ala440LeufsTer14 mutation of APC with SWISS-MODEL. Compared with wild type, the mutant leads to premature termination and potential loss of ability to bind with β-catenin. A440, Ala440; aa, amino acids; APC, Adenomatous polyposis coli.