Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy
Aims Nationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. Methods and results We sequenced 59 cardiomyopathy‐associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mu...
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Published in | ESC Heart Failure Vol. 6; no. 2; pp. 436 - 445 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
John Wiley & Sons, Inc
01.04.2019
John Wiley and Sons Inc |
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Abstract | Aims
Nationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published.
Methods and results
We sequenced 59 cardiomyopathy‐associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3‐Gln1061Ter, MYH7‐Arg1053Gln, and TPM1‐Asp175Asn) and a fourth major mutation MYH7‐Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow‐up, annual all‐cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266–91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098–1.363, P < 0.001) were independent predictors of HCM‐related mortality and life‐threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all‐cause or HCM‐related mortality between the two groups. Mortality due to HCM during 10 year follow‐up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM‐related deaths, of which 32% were sudden.
Conclusions
We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM‐related mutations in non‐sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM‐related deaths annually. |
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AbstractList | AimsNationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published.Methods and resultsWe sequenced 59 cardiomyopathy‐associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3‐Gln1061Ter, MYH7‐Arg1053Gln, and TPM1‐Asp175Asn) and a fourth major mutation MYH7‐Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow‐up, annual all‐cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266–91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098–1.363, P < 0.001) were independent predictors of HCM‐related mortality and life‐threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all‐cause or HCM‐related mortality between the two groups. Mortality due to HCM during 10 year follow‐up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM‐related deaths, of which 32% were sudden.ConclusionsWe identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM‐related mutations in non‐sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM‐related deaths annually. Aims Nationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. Methods and results We sequenced 59 cardiomyopathy‐associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3‐Gln1061Ter, MYH7‐Arg1053Gln, and TPM1‐Asp175Asn) and a fourth major mutation MYH7‐Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow‐up, annual all‐cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266–91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098–1.363, P < 0.001) were independent predictors of HCM‐related mortality and life‐threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all‐cause or HCM‐related mortality between the two groups. Mortality due to HCM during 10 year follow‐up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM‐related deaths, of which 32% were sudden. Conclusions We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM‐related mutations in non‐sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM‐related deaths annually. Abstract Aims Nationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. Methods and results We sequenced 59 cardiomyopathy‐associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes ( MYBPC3 , MYH7 , TPM1 , and MYL2 ). Previously reported mutations by our study group ( MYBPC3 ‐Gln1061Ter, MYH7 ‐Arg1053Gln, and TPM1 ‐Asp175Asn) and a fourth major mutation MYH7 ‐Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow‐up, annual all‐cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare ( n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266–91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098–1.363, P < 0.001) were independent predictors of HCM‐related mortality and life‐threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all‐cause or HCM‐related mortality between the two groups. Mortality due to HCM during 10 year follow‐up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM‐related deaths, of which 32% were sudden. Conclusions We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM‐related mutations in non‐sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM‐related deaths annually. Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. We sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3-Gln1061Ter, MYH7-Arg1053Gln, and TPM1-Asp175Asn) and a fourth major mutation MYH7-Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow-up, annual all-cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266-91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098-1.363, P < 0.001) were independent predictors of HCM-related mortality and life-threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all-cause or HCM-related mortality between the two groups. Mortality due to HCM during 10 year follow-up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM-related deaths, of which 32% were sudden. We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually. |
Author | Kuusisto, Johanna Hämäläinen, Liisa Kokkonen, Jorma Aalto‐Setälä, Katriina Kaartinen, Maija Heliö, Tiina Vangipurapu, Jagadish Nieminen, Markku S. Ilveskoski, Erkki Vanninen, Sari Raivo, Joose Kuulasmaa, Teemu Jääskeläinen, Pertti Laakso, Markku Melin, John |
AuthorAffiliation | 2 Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine University of Eastern Finland Kuopio Finland 9 Department of Medicine, Center for Medicine and Clinical Research University of Eastern Finland, Kuopio University Hospital P.O. Box 100 FIN‐70029 KYS Kuopio Finland 7 Vaasa Central Hospital Vaasa Finland 4 Heart Center Co., Institute of Biomedical Technology Tampere University Hospital, University of Tampere Tampere Finland 6 Heart Center Co. Tampere University Hospital Tampere Finland 1 Heart Center Kuopio University Hospital Kuopio Finland 5 Savonlinna Central Hospital Savonlinna Finland 8 Central Finland Central Hospital Jyväskylä Finland 3 Helsinki University Central Hospital Helsinki Finland |
AuthorAffiliation_xml | – name: 5 Savonlinna Central Hospital Savonlinna Finland – name: 6 Heart Center Co. Tampere University Hospital Tampere Finland – name: 2 Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine University of Eastern Finland Kuopio Finland – name: 8 Central Finland Central Hospital Jyväskylä Finland – name: 4 Heart Center Co., Institute of Biomedical Technology Tampere University Hospital, University of Tampere Tampere Finland – name: 3 Helsinki University Central Hospital Helsinki Finland – name: 7 Vaasa Central Hospital Vaasa Finland – name: 9 Department of Medicine, Center for Medicine and Clinical Research University of Eastern Finland, Kuopio University Hospital P.O. Box 100 FIN‐70029 KYS Kuopio Finland – name: 1 Heart Center Kuopio University Hospital Kuopio Finland |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30775854$$D View this record in MEDLINE/PubMed |
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Copyright | 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology. 2019. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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Keywords | Hypertrophic cardiomyopathy Genetics Mutation Targeted sequencing Mortality Outcome |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Helena Kervinen, Hyvinkää Hospital, Hyvinkää, Finland; Juha Mustonen, North Karelia Central Hospital, Joensuu, Finland; Jukka Juvonen, Kainuu Central Hospital, Kajaani, Finland; Mari Niemi, MD, Kokkola Central Hospital, Kokkola, Finland; Paavo Uusimaa, Oulu University Hospital, Oulu, Finland; Juhani Junttila, Oulu University Hospital, Oulu, Finland; Matti Kotila, Seinäjoki Central Hospital, Seinäjoki, Finland; Mikko Pietilä, Turku University Hospital, Turku, Finland; Heini Jyrkilä, University of Eastern Finland, Kuopio, Finland; Ilkka Mähönen, University of Tampere, Tampere, Finland; and Paula Vartia, University of Helsinki, Helsinki, Finland. Markku Laakso and Johanna Kuusisto contributed equally to this work. |
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Snippet | Aims
Nationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published.
Methods and... Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. We sequenced 59... Abstract Aims Nationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. Methods... AimsNationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published.Methods and... AIMSNationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. METHODS AND... |
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SubjectTerms | Cardiac Myosins - genetics Cardiac Myosins - metabolism Cardiology Cardiomyopathy Cardiomyopathy, Hypertrophic - genetics Cardiomyopathy, Hypertrophic - metabolism Cardiomyopathy, Hypertrophic - mortality DNA Mutational Analysis Female Finland - epidemiology Follow-Up Studies Forecasting Genetics Heterozygote Hospitals Humans Hypertrophic cardiomyopathy Male Medical prognosis Medical records Mortality Mutation NMR Nuclear magnetic resonance Original Original s Outcome Patients Pedigree Population Registries Sarcomeres - metabolism Sarcomeres - pathology Software Studies Survival Rate - trends Targeted sequencing Variables |
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Title | Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy |
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