Mutational heterogeneity, modifier genes, and environmental influences contribute to phenotypic diversity of arrhythmogenic cardiomyopathy
- PMID: 20570917
- DOI: 10.1161/CIRCGENETICS.109.935262
Mutational heterogeneity, modifier genes, and environmental influences contribute to phenotypic diversity of arrhythmogenic cardiomyopathy
Abstract
Background: Arrhythmogenic cardiomyopathy is one of the leading causes of sudden cardiac death in the < or =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.
Similar articles
-
Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy.Circulation. 2020 Jun 9;141(23):1872-1884. doi: 10.1161/CIRCULATIONAHA.119.044934. Epub 2020 May 6. Circulation. 2020. PMID: 32372669 Free PMC article.
-
The role of genetics in cardiovascular disease: arrhythmogenic cardiomyopathy.Eur Heart J. 2020 Apr 7;41(14):1393-1400. doi: 10.1093/eurheartj/ehaa141. Eur Heart J. 2020. PMID: 32191298 Review.
-
Role of novel DSP_p.Q986X genetic variation in arrhythmogenic right ventricular cardiomyopathy.Eur J Med Genet. 2013 Oct;56(10):541-5. doi: 10.1016/j.ejmg.2013.08.001. Epub 2013 Aug 14. Eur J Med Genet. 2013. PMID: 23954618
-
The changing spectrum of arrhythmogenic (right ventricular) cardiomyopathy.Cell Tissue Res. 2012 May;348(2):319-23. doi: 10.1007/s00441-012-1402-z. Epub 2012 Apr 4. Cell Tissue Res. 2012. PMID: 22476658 Review.
-
Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression.Circulation. 2007 Apr 3;115(13):1710-20. doi: 10.1161/CIRCULATIONAHA.106.660241. Epub 2007 Mar 19. Circulation. 2007. PMID: 17372169
Cited by
-
Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction.Biomedicines. 2024 Apr 30;12(5):985. doi: 10.3390/biomedicines12050985. Biomedicines. 2024. PMID: 38790949 Free PMC article.
-
Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy.Nat Cardiovasc Res. 2023;2(12):1262-1276. doi: 10.1038/s44161-023-00378-9. Epub 2023 Dec 7. Nat Cardiovasc Res. 2023. PMID: 38665939 Free PMC article.
-
Modeling incomplete penetrance in arrhythmogenic cardiomyopathy by human induced pluripotent stem cell derived cardiomyocytes.Comput Struct Biotechnol J. 2023 Feb 17;21:1759-1773. doi: 10.1016/j.csbj.2023.02.029. eCollection 2023. Comput Struct Biotechnol J. 2023. PMID: 36915380 Free PMC article.
-
Echocardiography phenotyping in murine genetic reference population of BXD strains reveals significant QTLs associated with cardiac function and morphology.Physiol Genomics. 2023 Feb 1;55(2):51-66. doi: 10.1152/physiolgenomics.00120.2022. Epub 2022 Dec 19. Physiol Genomics. 2023. PMID: 36534598 Free PMC article.
-
Application of an F0-based genetic assay in adult zebrafish to identify modifier genes of an inherited cardiomyopathy.Dis Model Mech. 2023 May 1;16(5):dmm049427. doi: 10.1242/dmm.049427. Epub 2022 Jun 23. Dis Model Mech. 2023. PMID: 35481478 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical