Mutation Analysis of the APC Gene in a Chinese FAP Pedigree with Unusual Phenotype

Background and Aim. Germline mutations of the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP), an autosomal dominant inherited disease mainly characterized by colorectal adenomatous polyposis. Genetic studies of FAP have shown that somatic APC mutations are dependent on the position of the germline APC mutation. However, the molecular mechanism underlying these genotype-phenotype associations for APC in Chinese remain largely unknown. Patients and Methods. In this study, we investigated the APC gene mutation in a Chinese FAP family by systematic screening with multiplex ligation-dependent probe amplification (MLPA), denaturing high-performance liquid chromatography (dHPLC), and DNA sequencing. Promoter methylation was detected by methylation-specific PCR. Results. The identical germline mutation c.1999 C>T (Q667X) of APC was identified in 5 affected members, among which 2 members carried somatic mutations of APC, one with promoter hypermethylation and the other with loss of wild-type allele in their adenomas. The somatic mutations were shown connected with the disease severity, demonstrating a unique genotype-phenotype association in this FAP pedigree. Conclusion. The study revealed the existence of novel pathogenic mutations in Chinese patients with FAP. Somatic mutations are of particular interest because of the unusual phenotypic features shown by patients.