Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders

M. Juhani Junttila, Lauri Holmström, Katri Pylkäs, Tuomo Mantere, Kari Kaikkonen, Katja Porvari, Marja Leena Kortelainen, Lasse Pakanen, Risto Kerkelä, Robert J Myerburg, Heikki V. Huikuri

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Myocardial fibrosis is a common postmortem finding among young individuals with sudden cardiac death. Because there is no known single cause, we tested the hypothesis that some cases of myocardial fibrosis in the absence of identifiable causes (primary myocardial fibrosis [PMF]) are associated with genetic variants. Methods: Tissue was obtained at autopsy from 4031 consecutive individuals with sudden cardiac death in Northern Finland, among whom PMF was the only structural finding in 145 subjects with sudden cardiac death. We performed targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function when autopsies did not identify a secondary basis for myocardial fibrosis. All variants with an effect on protein and with a minor allele frequency <0.01 were classified as pathogenic or variants of uncertain significance on the basis of American College of Medical Genetics consensus guidelines. Results: Among the 96 specimens with DNA passing quality control (66%), postmortem genetic tests identified 24 variants of known or uncertain significance in 26 subjects (27%). Ten were pathogenic/likely pathogenic variants in 10 subjects (10%), and 14 were variants of uncertain significance in 11 genes among 16 subjects (17%). Five variants were in genes associated with arrhythmogenic right ventricular cardiomyopathy, 6 in hypertrophic cardiomyopathy-associated genes, and 11 in dilated cardiomyopathy-associated genes; 2 were not associated with these disorders. Four unique variants of uncertain significance cosegregated among multiple unrelated subjects with PMF. No pathogenic/likely pathogenic variants were detected in ion channel-encoding genes. Conclusions: A large proportion of subjects with PMF at autopsy had variants in genes associated with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy without autopsy findings of those diseases, suggesting that PMF can be an alternative phenotypic expression of structural disease-associated genetic variants or that risk-associated fibrosis was expressing before the primary disease. These findings have clinical implications for postmortem genetic testing and family risk profiling.

Original languageEnglish (US)
Pages (from-to)2716-2726
Number of pages11
JournalCirculation
Volume137
Issue number25
DOIs
StatePublished - Jun 19 2018

Fingerprint

Fibrosis
Phenotype
Autopsy
Sudden Cardiac Death
Genes
Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Ion Channels
Arrhythmogenic Right Ventricular Dysplasia
Inborn Genetic Diseases
Genetic Testing
Finland
Cardiomyopathies
Gene Frequency
Quality Control
Guidelines
DNA
Proteins

Keywords

  • cardiomyopathies
  • death, cardiac, sudden
  • fibrosis
  • genetics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Junttila, M. J., Holmström, L., Pylkäs, K., Mantere, T., Kaikkonen, K., Porvari, K., ... Huikuri, H. V. (2018). Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders. Circulation, 137(25), 2716-2726. https://doi.org/10.1161/CIRCULATIONAHA.117.032175

Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders. / Junttila, M. Juhani; Holmström, Lauri; Pylkäs, Katri; Mantere, Tuomo; Kaikkonen, Kari; Porvari, Katja; Kortelainen, Marja Leena; Pakanen, Lasse; Kerkelä, Risto; Myerburg, Robert J; Huikuri, Heikki V.

In: Circulation, Vol. 137, No. 25, 19.06.2018, p. 2716-2726.

Research output: Contribution to journalArticle

Junttila, MJ, Holmström, L, Pylkäs, K, Mantere, T, Kaikkonen, K, Porvari, K, Kortelainen, ML, Pakanen, L, Kerkelä, R, Myerburg, RJ & Huikuri, HV 2018, 'Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders', Circulation, vol. 137, no. 25, pp. 2716-2726. https://doi.org/10.1161/CIRCULATIONAHA.117.032175
Junttila MJ, Holmström L, Pylkäs K, Mantere T, Kaikkonen K, Porvari K et al. Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders. Circulation. 2018 Jun 19;137(25):2716-2726. https://doi.org/10.1161/CIRCULATIONAHA.117.032175
Junttila, M. Juhani ; Holmström, Lauri ; Pylkäs, Katri ; Mantere, Tuomo ; Kaikkonen, Kari ; Porvari, Katja ; Kortelainen, Marja Leena ; Pakanen, Lasse ; Kerkelä, Risto ; Myerburg, Robert J ; Huikuri, Heikki V. / Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders. In: Circulation. 2018 ; Vol. 137, No. 25. pp. 2716-2726.
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abstract = "Background: Myocardial fibrosis is a common postmortem finding among young individuals with sudden cardiac death. Because there is no known single cause, we tested the hypothesis that some cases of myocardial fibrosis in the absence of identifiable causes (primary myocardial fibrosis [PMF]) are associated with genetic variants. Methods: Tissue was obtained at autopsy from 4031 consecutive individuals with sudden cardiac death in Northern Finland, among whom PMF was the only structural finding in 145 subjects with sudden cardiac death. We performed targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function when autopsies did not identify a secondary basis for myocardial fibrosis. All variants with an effect on protein and with a minor allele frequency <0.01 were classified as pathogenic or variants of uncertain significance on the basis of American College of Medical Genetics consensus guidelines. Results: Among the 96 specimens with DNA passing quality control (66{\%}), postmortem genetic tests identified 24 variants of known or uncertain significance in 26 subjects (27{\%}). Ten were pathogenic/likely pathogenic variants in 10 subjects (10{\%}), and 14 were variants of uncertain significance in 11 genes among 16 subjects (17{\%}). Five variants were in genes associated with arrhythmogenic right ventricular cardiomyopathy, 6 in hypertrophic cardiomyopathy-associated genes, and 11 in dilated cardiomyopathy-associated genes; 2 were not associated with these disorders. Four unique variants of uncertain significance cosegregated among multiple unrelated subjects with PMF. No pathogenic/likely pathogenic variants were detected in ion channel-encoding genes. Conclusions: A large proportion of subjects with PMF at autopsy had variants in genes associated with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy without autopsy findings of those diseases, suggesting that PMF can be an alternative phenotypic expression of structural disease-associated genetic variants or that risk-associated fibrosis was expressing before the primary disease. These findings have clinical implications for postmortem genetic testing and family risk profiling.",
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AU - Kaikkonen, Kari

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AU - Kortelainen, Marja Leena

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AB - Background: Myocardial fibrosis is a common postmortem finding among young individuals with sudden cardiac death. Because there is no known single cause, we tested the hypothesis that some cases of myocardial fibrosis in the absence of identifiable causes (primary myocardial fibrosis [PMF]) are associated with genetic variants. Methods: Tissue was obtained at autopsy from 4031 consecutive individuals with sudden cardiac death in Northern Finland, among whom PMF was the only structural finding in 145 subjects with sudden cardiac death. We performed targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function when autopsies did not identify a secondary basis for myocardial fibrosis. All variants with an effect on protein and with a minor allele frequency <0.01 were classified as pathogenic or variants of uncertain significance on the basis of American College of Medical Genetics consensus guidelines. Results: Among the 96 specimens with DNA passing quality control (66%), postmortem genetic tests identified 24 variants of known or uncertain significance in 26 subjects (27%). Ten were pathogenic/likely pathogenic variants in 10 subjects (10%), and 14 were variants of uncertain significance in 11 genes among 16 subjects (17%). Five variants were in genes associated with arrhythmogenic right ventricular cardiomyopathy, 6 in hypertrophic cardiomyopathy-associated genes, and 11 in dilated cardiomyopathy-associated genes; 2 were not associated with these disorders. Four unique variants of uncertain significance cosegregated among multiple unrelated subjects with PMF. No pathogenic/likely pathogenic variants were detected in ion channel-encoding genes. Conclusions: A large proportion of subjects with PMF at autopsy had variants in genes associated with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy without autopsy findings of those diseases, suggesting that PMF can be an alternative phenotypic expression of structural disease-associated genetic variants or that risk-associated fibrosis was expressing before the primary disease. These findings have clinical implications for postmortem genetic testing and family risk profiling.

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