Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy
| Autor: | Nakita Laing, Simon N. Pimstone, Thomas Meitinger, Ashley Chin, Ntobeko B A Ntusi, Tim Matthias Strom, Thomas Wieland, Maryam Fish, Maria Christina Kotta, Gasnat Shaboodien, Sarah Kraus, Peter J. Schwartz, Bongani M. Mayosi, Davide Gentilini, Gianfranco Parati, Guillaume Paré, Elisa Mastantuono, Lia Crotti, Christopher Horsfall, Michael Chong |
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| Přispěvatelé: | Mayosi, B, Fish, M, Shaboodien, G, Mastantuono, E, Kraus, S, Wieland, T, Kotta, M, Chin, A, Laing, N, Ntusi, N, Chong, M, Horsfall, C, Pimstone, S, Gentilini, D, Parati, G, Strom, T, Meitinger, T, Pare, G, Schwartz, P, Crotti, L |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
arrhythmogenic right ventricular dysplasia Adult Male Pathology medicine.medical_specialty Adolescent MED/03 - GENETICA MEDICA Mutation Missense 030204 cardiovascular system & hematology Biology medicine.disease_cause CDH2 Right ventricular cardiomyopathy 03 medical and health sciences 0302 clinical medicine Genetic Antigens CD Genetics medicine Exome Exome sequencing Genetics (clinical) Mutation cardiomyopathie Arrhythmogenic Right Ventricular Dysplasia Cadherins Cardiomyopathies Genetic heterogeneity Cadherin MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE medicine.disease Molecular biology Arrhythmogenic right ventricular dysplasia 030104 developmental biology cadherin Amino Acid Substitution Female mutation Cardiology and Cardiovascular Medicine Human |
| Zdroj: | Circ. Cardiovasc. Genet. 10:e001605 (2017) |
| Popis: | Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families. Methods and Results— Whole exome sequencing was performed on 2 cousins with ARVC. Validation of 13 heterozygous variants that survived internal quality and frequency filters was performed by Sanger sequencing. These variants were also genotyped in all family members to establish genotype–phenotype cosegregation. High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 ( CDH2 ) gene in unrelated genotype-negative patients with ARVC. In a 3-generation family, we identified by whole exome sequencing a novel mutation in CDH2 (c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. The CDH2 c.686A>C variant was not present in >200 000 chromosomes available through public databases, which changes a conserved amino acid of cadherin 2 protein and is supported as the causal mutation by parametric linkage analysis. We subsequently screened 73 genotype-negative ARVC probands tested previously for mutations in known ARVC genes and found an additional likely pathogenic variant in CDH2 (c.1219G>A, p.Asp407Asn). CDH2 encodes cadherin 2 (also known as N-cadherin), a protein that plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis. Conclusions— These data implicate CDH2 mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy. |
| Databáze: | OpenAIRE |
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