Targeted next‐generation sequencing approach for molecular genetic diagnosis of hereditary colorectal cancer: Identification of a novel single nucleotide germline insertion in adenomatous polyposis coli gene causes familial adenomatous polyposis

Autor: Chen Xu, Guoru Zhao, Shengyun Liang, Yongjun Yu, Xipeng Zhang, Zhao Zhang, Mingsen Li, Subrata Kumar Dey, Yuwei Li, Dan Wang
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Adult
Male
Adenomatous polyposis coli
Colorectal cancer
Adenomatous Polyposis Coli Protein
colorectal cancer
030105 genetics & heredity
medicine.disease_cause
Polymorphism
Single Nucleotide
Frameshift mutation
Familial adenomatous polyposis
03 medical and health sciences
Exon
symbols.namesake
single nucleotide deletion
Germline mutation
APC gene
Loss of Function Mutation
familial adenomatous polyposis
Genetics
medicine
Humans
Genetic Testing
Molecular Biology
Genetics (clinical)
Germ-Line Mutation
Sanger sequencing
Mutation
biology
business.industry
Original Articles
Sequence Analysis
DNA
Middle Aged
medicine.disease
digestive system diseases
Pedigree
030104 developmental biology
Adenomatous Polyposis Coli
Cancer research
biology.protein
symbols
Original Article
Female
Chinese population
business
targeted next‐generation sequencing
Zdroj: Molecular Genetics & Genomic Medicine
ISSN: 2324-9269
Popis: Background Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease which primarily manifested with developing adenomas or polyps in colon or rectum. It is caused by the germline mutations in adenomatous polyposis coli (APC) gene. Patients with FAP are usually manifested with “hundreds or even thousands” adenomas or polyps in colon or rectum. However, without proper clinical diagnosis and timely surgical interventions, colorectal adenomas, or polyps gradually increase in size and in numbers which finally leads to colorectal cancer (CRC) at the mean age of 36 years of the patient. Methods In this study, we identified a family with FAP. In this family, FAP has been diagnosed clinically based on symptoms, medical test reports, and positive family history for three generations. In order to unveil the molecular genetic consequences underlying the disease phenotype, we performed next‐generation sequencing with a customized and designed panel of genes reported to be associated with hereditary CRC. The variant identified by next‐generation sequencing has been validated by Sanger sequencing. Results A heterozygous novel insertion [c.3992_3993insA; p.Thr1332Asnfs*10] in exon 16 of APC gene has been identified. This novel insertion is cosegregated well with the FAP phenotype among all the affected members of this family. This mutation causes a frameshift by the formation of a premature stop codon which finally results in the formation of a truncated APC protein of 1,342 amino acids instead of the wild type APC protein of 2,843 amino acids. Hence, this is a loss‐of‐function mutation. This mutation was not found in unaffected family members or in normal control individuals. Conclusion Our present study emphasizes the importance of a novel approach of the gene panel‐based high‐throughput sequencing technology for easy and rapid screening for patients with FAP or CRC which will help the clinician for follow‐up and management.
Databáze: OpenAIRE
Externí odkaz: