Detection of APC mosaicism by next-generation sequencing in an FAP patient.

Familial adenomatous polyposis (FAP) of the colon is characterized by multiple polyps in the intestine and extra-colonic manifestations. Most FAP cases are caused by a germline mutation in the tumor-suppressor gene APC, but some cases of adenomatous polyposis result from germline mutations in MUTYH, POLD1 or POLE. Although sequence analysis of APC by the Sanger method is routinely performed for genetic testing, there remain cases whose mutations are not detected by the analysis. Next-generation sequencing has enabled us to analyze the comprehensive human genome, improving the chance of identifying disease causative variants. In this study, we conducted whole-genome sequencing of a sporadic FAP patient in which we did not find any pathogenic APC mutations by the conventional Sanger sequencing. Whole-genome sequencing and subsequent deep sequencing identified a mosaic mutation of c.3175G>T, p.E1059X in ~12% of his peripheral leukocytes. Additional deep sequencing of his buccal mucosa, hair follicles, non-cancerous mucosa of the stomach and colon disclosed that these tissues harbored the APC mutation at different frequencies. Our data implied that genetic analysis by next-generation sequencing is an effective strategy to identify genetic mosaicism in hereditary diseases.

Attenuated familial adenomatous polyposis with desmoids caused by an APC mutation.

We present here a case of attenuated familial adenomatous polyposis (AFAP) with a family history of desmoids and thyroid tumors. This patient had no colonic polyps but did have multiple desmoids. Genetic analysis identified a 4-bp deletion in codon 2644 (c.7932_7935delTTAT: p.Tyr2645LysfsX14) of the adenomatous polyposis coli (APC) gene. In cases with limited numbers of colonic polyps and desmoids, AFAP may be caused by a mutation in the 3' region of APC.