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Mutational Heterogeneity, Modifier Genes, and Environmental Influences Contribute to Phenotypic Diversity of Arrhythmogenic Cardiomyopathy

Sen-Chowdhry, S; Syrris, P; Pantazis, A; Quarta, G; McKenna, WJ; Chambers, JC; (2010) Mutational Heterogeneity, Modifier Genes, and Environmental Influences Contribute to Phenotypic Diversity of Arrhythmogenic Cardiomyopathy. CIRC-CARDIOVASC GENE , 3 (4) 323 - U29. 10.1161/CIRCGENETICS.109.935262.

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Abstract

Background-Arrhythmogenic cardiomyopathy is one of the leading causes of sudden cardiac death in the <= 35-year age group. The broad phenotypic spectrum encompasses left-dominant and biventricular subtypes, characterized by early left ventricular involvement, as well as the classic right-dominant form, better known as arrhythmogenic right ventricular cardiomyopathy. Mendelian inheritance patterns are accompanied by incomplete penetrance and variable expressivity, the latter manifesting as diversity in morphology, arrhythmic burden, and clinical outcomes.Methods and Results-To investigate the role of mutational heterogeneity, genetic modifiers and environmental influences in arrhythmogenic cardiomyopathy, we studied phenotype variability in 9 quantitative traits among an affected-only sample of 231 cases from 48 families. Heritability was estimated by variance component analysis as a guide to the combined influence of mutational and genetic background heterogeneity. Nested ANOVA was used to distinguish mutational and genetic modifier effects. Heritability estimates ranged from 20% to 77%, being highest for left ventricular ejection fraction and right-to-left ventricular volume ratio and lowest for the ventricular arrhythmia grade, suggesting differing genetic and environmental contributions to these traits. ANOVA models indicated a predominant mutation effect for the left ventricular lesion score, an indicator of the extent of fat and late enhancement on cardiovascular magnetic resonance. In contrast, the modifier genetic effect appeared significant for right ventricular end-diastolic volume, ejection fraction, and lesion score; left ventricular ejection fraction; ventricular volume ratio; and arrhythmic events.Conclusions-Systematic investigation of modifier genes and environmental influences will be pivotal to understanding clinical diversity in arrhythmogenic cardiomyopathy, refining prognostication, and developing targeted therapies. (Circ Cardiovasc Genet. 2010;3:323-330.)

Type: Article
Title: Mutational Heterogeneity, Modifier Genes, and Environmental Influences Contribute to Phenotypic Diversity of Arrhythmogenic Cardiomyopathy
DOI: 10.1161/CIRCGENETICS.109.935262
Keywords: arrhythmia, cardiomyopathy, sudden cardiac death, genetics, imaging, RIGHT-VENTRICULAR CARDIOMYOPATHY, IDIOPATHIC DILATED CARDIOMYOPATHY, CARDIOVASCULAR MAGNETIC-RESONANCE, TASK-FORCE CRITERIA, HYPERTROPHIC CARDIOMYOPATHY, DIASTOLIC FUNCTION, PEDIGREE ANALYSIS, CARVAJAL-SYNDROME, CLINICAL PROFILE, BINDING-PROTEIN
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: http://discovery.ucl.ac.uk/id/eprint/130231
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