Dataset Information

Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer.

ABSTRACT: Familial adenomatous polyposis (FAP) is an autosomal-dominant condition characterized by the presence of multiple colorectal adenomas, caused by germline variants in the adenomatous polyposis coli (APC) gene. More than 300 germline variants have been characterized. The detection of novel variants is important to understand the mechanisms of pathophysiology. We identified a novel pathogenic germline variant using next-generation sequencing (NGS) in a proband patient. The variant is a complex rearrangement (c.422+1123_532-577 del ins 423-1933_423-1687 inv) that generates a complete deletion of exon 5 of the APC gene. To study the variant in other family members, we designed an endpoint PCR method followed by Sanger sequencing. The variant was identified in the proband patient's mother, one daughter, her brother, two cousins, a niece, and a second nephew. In patients where the variant was identified, we found atypical clinical symptoms, including mandibular, ovarian, breast, pancreatic, and gastric cancer. Genetic counseling and cancer prevention strategies were provided for the family. According to the American College of Medical Genetics (ACMG) guidelines, this novel variant is considered a PVS1 variant (very strong evidence of pathogenicity), and it can be useful in association with clinical data for early surveillance and suitable treatment.

SUBMITTER: Garza-Rodriguez ML

PROVIDER: S-EPMC7997431 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer.

Garza-Rodríguez María Lourdes ML Treviño Víctor V Pérez-Maya Antonio Alí AA Rodríguez-Gutiérrez Hazyadee Frecia HF González-Escamilla Moisés M Elizondo-Riojas Miguel Ángel MÁ Ramírez-Correa Genaro A GA Vidal-Gutiérrez Oscar O Burciaga-Flores Carlos Horacio CH Pérez-Ibave Diana Cristina DC

Diagnostics (Basel, Switzerland) 20210228 3

Familial adenomatous polyposis (FAP) is an autosomal-dominant condition characterized by the presence of multiple colorectal adenomas, caused by germline variants in the adenomatous polyposis coli (<i>APC</i>) gene. More than 300 germline variants have been characterized. The detection of novel variants is important to understand the mechanisms of pathophysiology. We identified a novel pathogenic germline variant using next-generation sequencing (NGS) in a proband patient. The variant is a compl ...[more]

PMID: 33670908

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Project description:BackgroundFamilial adenomatous polyposis (FAP) is caused by pathogenic germline variants in the APC gene. To date, multiple pathogenic variants in coding regions, splice sites, and deep intronic regions have been revealed. However, there are still pathogenic variants that remain unidentified.MethodsTwenty-nine primer pairs flanking exons 2-16 (i.e., coding exons 1-15) of APC and their exon-intron junctions were used for germline pathogenic variant screening in Southern Thai patients with familial adenomatous polyposis (FAP). Transcription analysis was performed to confirm the pathogenicity of a splice site deletion of intron 10. Family members were interviewed for clinical histories. Blood samples were collected from 18 family members for a segregation study. Subsequently, clinical data of affected members were collected from the hospital databases.ResultsWe found a distinct heterozygous 16-bp deletion at the splice donor site of intron 10 leading to a skipping of exon 10 which was confirmed by transcript analysis (APC: c 1312 + 4_1312 + 19del, r.934_1312del). Predictive testing for the pathogenic APC variant in 18 of the proband's family members (ten healthy and eight affected) from three generations showed the same heterozygous germline pathogenic variant in eight affected adult members (15-62 years old) and two children (7 and 10 years old). Seven of the ten carriers of the disease-causing variant had undergone colonoscopy, and colonic polyps were found in all cases, which confirmed the segregation of the inherited pathogenic variant. The phenotypic spectrum was found to vary within the family; and some affected family members exhibited extracolonic manifestations.ConclusionsTo our knowledge, the pathogenic APC variant, c.1312 + 4_1312 + 19del, r.934_1312del, has not previously been reported. This study is one of the few reports describing the phenotypic consequences of a pathogenic APC variant in a high number of affected family members.

Dataset Information

Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer.

Publications

Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer.

Similar Datasets

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