Dataset Information

APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation.

ABSTRACT: APC and MUTYH genes are mutated in 70?90% and 10?30% of familial adenomatous polyposis cases (FAP) respectively. An association between mutation localization and FAP clinical phenotype is reported. The aims of this study were to determine APC and MUTYH mutational status in a small cohort of FAP patients and to evaluate the genotype-phenotype correlation in mutated patients. Here, we report the identification of a novel APC germline mutation, c.510_511insA. Overall, mutational analysis showed pathogenic mutations in 6/10 patients: 5/10 in APC and 1/10 in MUTYH. Additionally, we found three variants of unknown significance in MUTYH gene that showed no evidence of possible splicing defects by in silico analysis. Molecular analysis was also extended to family members of mutated patients. A genotype-phenotype correlation was observed for colonic signs whereas a variation of disease onset age was revealed for the same mutation. Moreover, we found an intrafamilial variability of FAP onset age. Regarding extracolonic manifestations, the development of desmoid tumors was related to surgery and not to mutation position, while a genotype-phenotype correspondence was observed for the onset of thyroid or gastric cancer. These findings can be useful in association to clinical data for early surveillance and suitable treatment of FAP patients.

SUBMITTER: D'Elia G

PROVIDER: S-EPMC6071208 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation.

D'Elia Giovanna G Caliendo Gemma G Casamassimi Amelia A Cioffi Michele M Molinari Anna Maria AM Vietri Maria Teresa MT

Genes 20180627 7

APC and MUTYH genes are mutated in 70⁻90% and 10⁻30% of familial adenomatous polyposis cases (FAP) respectively. An association between mutation localization and FAP clinical phenotype is reported. The aims of this study were to determine APC and MUTYH mutational status in a small cohort of FAP patients and to evaluate the genotype-phenotype correlation in mutated patients. Here, we report the identification of a novel APC germline mutation, c.510_511insA. Over ...[more]

PMID: 29954149

Similar Datasets

Project description:PURPOSE: To screen a cohort of corneal dystrophy patients from North India for mutations in the transforming growth factor beta induced (TGFBI) gene, to correlate genotypes to phenotypes, to describe structural implications of various mutations on protein function, and to discuss the implications for diagnosis. METHODS: Eighty affected individuals from 61 unrelated families, who were diagnosed with autosomal dominant granular and/or lattice corneal dystrophy, were recruited for the study. Detailed clinical evaluation was undertaken for these patients to establish their corneal phenotypes. Genomic DNA was isolated from peripheral blood samples and all exons of TGFBI were screened for mutations by polymerase chain reaction (PCR) and direct DNA sequencing. Protein molecular dynamics (MD) simulations were performed for the mutations detected to assess the changes in protein structure. RESULTS: The most common mutations seen were Arg555Trp and Arg124Cys. Two novel mutations, Ser516Arg (c.DNA1548C>G), with a phenotype similar to granular corneal dystrophy I (GCDI), and Leu559Val (c.DNA1675T>G), with an atypical phenotype closely resembling epithelial basement membrane dystrophy/map dot fingerprint dystrophy, were identified. Protein modeling studies involving wild type and mutant protein indicated that the Leu559Val is a destabilizing mutation and that Ser516Arg could adversely affect the specific binding of Fas1 domain 4 with other proteins. In addition, two single-nucleotide polymorphisms, rs4669 and rs11331170, were also identified. Mutations were not identified in 8 affected individuals, 6 of whom were diagnosed with bowman layer dystrophy and 2 with lattice corneal dystrophy. CONCLUSIONS: This is the first comprehensive report of TGFBI mutations covering a large part of North India. Identification of novel mutations, the presence of phenotypic variability, and the genetic heterogeneity seen in our cases stress the need for mandatory screening of TGFBI for precise diagnosis and classification of corneal dystrophies.

Project description:BackgroundFamilial adenomatous polyposis (FAP) is an autosomal dominant-inherited colorectal cancer syndrome, caused by germline mutations in the APC gene. Recently, biallelic mutations in MUTYH have also been identified in patients with multiple colorectal adenomas and in APC-negative patients with FAP. The aim of this work is therefore to determine the frequency of APC and MUTYH mutations among FAP families from two Spanish populations.MethodsEighty-two unrelated patients with classical or attenuated FAP were screened for APC germline mutations. MUTYH analysis was then conducted in those APC-negative families and in 9 additional patients from a previous study. Direct sequencing, SSCP analysis and TaqMan genotyping were used to identify point and frameshift mutations, meanwhile large rearrangements in the APC gene were screened by multiplex ligation-dependent probe amplification (MLPA).ResultsAPC germline mutations were found in 39% of the patients and, despite the great number of genetic variants described so far in this gene, seven new mutations were identified. The two hotspots at codons 1061 and 1309 of the APC gene accounted for 9,4% of the APC-positive families, although they were underrepresented in Galician samples. The deletion at codon 1061 was not found in 19 APC-positive Galician patients but represented 23% of the Catalonian positive families (p = 0,058). The same trend was observed at codon 1309, even though statistical analysis showed no significance between populations. Twenty-four percent of the APC-negative patients carried biallelic MUTYH germline mutations, and showed an attenuated polyposis phenotype generally without extracolonic manifestations. New genetic variants were found, as well as the two hotspots already reported (p.Tyr165Cys and p.Gly382Asp).ConclusionThe results we present indicate that in Galician patients the frequency of the hotspot at codon 1061 in APC differs significantly from the Catalonian and also other Caucasian populations. Similar results had already been obtained in a previous study and could be due to the genetic isolation of the Galician population. MUTYH analysis is also recommended for all APC-negative families, even if a recessive inheritance is not confirmed.

Dataset Information

APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation.

Publications

<i>APC</i> and <i>MUTYH</i> Analysis in FAP Patients: A Novel Mutation in <i>APC</i> Gene and Genotype-Phenotype Correlation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets