M Juhani Junttila1, Lauri Holmström2, Katri Pylkäs3, Tuomo Mantere3, Kari Kaikkonen2, Katja Porvari4, Marja-Leena Kortelainen4, Lasse Pakanen4,5, Risto Kerkelä6, Robert J Myerburg7, Heikki V Huikuri2. 1. Research Unit of Internal Medicine, University of Oulu and University Hospital of Oulu, Finland (M.J.J., L.H., K.K., H.V.H.) juhani.junttila@oulu.fi. 2. Research Unit of Internal Medicine, University of Oulu and University Hospital of Oulu, Finland (M.J.J., L.H., K.K., H.V.H.). 3. Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu (K. Pylkäs, T.M.). 4. Department of Forensic Medicine, Research Unit of Internal Medicine, Medical Research Center Oulu (K, Porvari, M.-L.K., L.P.). 5. National Institute for Health and Welfare, Forensic Medicine Unit, Oulu, Finland (L.P.). 6. Research Unit of Biomedicine (R.K.), University of Oulu, Finland. 7. Division of Cardiology, University of Miami Miller School of Medicine, FL (R.J.M.).
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.
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.
Authors: Mercedes Iglesias; Tomas Ripoll-Vera; Consuelo Perez-Luengo; Ana Belen García; Susana Moyano; Juan Carlos Canos; Juan Carlos Borondo; Jorge Alvarez; Damian Heine-Suñer; Bernardino Barcelo Journal: J Clin Med Date: 2021-04-21 Impact factor: 4.241
Authors: Ruizhu Lin; Lea Rahtu-Korpela; Johanna Magga; Johanna Ulvila; Julia Swan; Anna Kemppi; Lasse Pakanen; Katja Porvari; Heikki Huikuri; Juhani Junttila; Risto Kerkelä Journal: Mol Ther Nucleic Acids Date: 2020-04-08 Impact factor: 8.886
Authors: Mausam Patel; Daniela Rodriguez; Keyvan Yousefi; Krista John-Williams; Armando J Mendez; Ronald B Goldberg; Anastasios Lymperopoulos; Leonardo J Tamariz; Jeffrey J Goldberger; Robert J Myerburg; Juhani Junttila; Lina A Shehadeh Journal: Front Cardiovasc Med Date: 2020-11-30
Authors: Juha H Vähätalo; Lauri T A Holmström; Katri Pylkäs; Sini Skarp; Katja Porvari; Lasse Pakanen; Kari S Kaikkonen; Juha S Perkiömäki; Risto Kerkelä; Heikki V Huikuri; Robert J Myerburg; M Juhani Junttila Journal: Front Cardiovasc Med Date: 2022-01-11
Authors: Lauri Holmström; Katri Pylkäs; Anna Tervasmäki; Juha Vähätalo; Katja Porvari; Lasse Pakanen; Kari S Kaikkonen; Juha S Perkiömäki; Antti M Kiviniemi; Risto Kerkelä; Olavi Ukkola; Robert J Myerburg; Heikki V Huikuri; Juhani Junttila Journal: Sci Rep Date: 2021-05-27 Impact factor: 4.379