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Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy
AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS : In a...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380059/ https://www.ncbi.nlm.nih.gov/pubmed/34263907 http://dx.doi.org/10.1093/eurheartj/ehab424 |
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author | Lopes, Luis R Garcia-Hernández, Soledad Lorenzini, Massimiliano Futema, Marta Chumakova, Olga Zateyshchikov, Dmitry Isidoro-Garcia, Maria Villacorta, Eduardo Escobar-Lopez, Luis Garcia-Pavia, Pablo Bilbao, Raquel Dobarro, David Sandin-Fuentes, Maria Catalli, Claudio Gener Querol, Blanca Mezcua, Ainhoa Garcia Pinilla, Jose Bloch Rasmussen, Torsten Ferreira-Aguar, Ana Revilla-Martí, Pablo Basurte Elorz, Maria Teresa Bautista Paves, Alicia Ramon Gimeno, Juan Figueroa, Ana Virginia Franco-Gutierrez, Raul Fuentes-Cañamero, Maria Eugenia Martinez Moreno, Marina Ortiz-Genga, Martin Piqueras-Flores, Jesus Analia Ramos, Karina Rudzitis, Ainars Ruiz-Guerrero, Luis Stein, Ricardo Triguero-Bocharán, Mayte de la Higuera, Luis Ochoa, Juan Pablo Abu-Bonsrah, Dad Kwok, Cecilia Y T Smith, Jacob B Porrello, Enzo R Akhtar, Mohammed M Jager, Joanna Ashworth, Michael Syrris, Petros Elliott, David A Monserrat, Lorenzo Elliott, Perry M |
author_facet | Lopes, Luis R Garcia-Hernández, Soledad Lorenzini, Massimiliano Futema, Marta Chumakova, Olga Zateyshchikov, Dmitry Isidoro-Garcia, Maria Villacorta, Eduardo Escobar-Lopez, Luis Garcia-Pavia, Pablo Bilbao, Raquel Dobarro, David Sandin-Fuentes, Maria Catalli, Claudio Gener Querol, Blanca Mezcua, Ainhoa Garcia Pinilla, Jose Bloch Rasmussen, Torsten Ferreira-Aguar, Ana Revilla-Martí, Pablo Basurte Elorz, Maria Teresa Bautista Paves, Alicia Ramon Gimeno, Juan Figueroa, Ana Virginia Franco-Gutierrez, Raul Fuentes-Cañamero, Maria Eugenia Martinez Moreno, Marina Ortiz-Genga, Martin Piqueras-Flores, Jesus Analia Ramos, Karina Rudzitis, Ainars Ruiz-Guerrero, Luis Stein, Ricardo Triguero-Bocharán, Mayte de la Higuera, Luis Ochoa, Juan Pablo Abu-Bonsrah, Dad Kwok, Cecilia Y T Smith, Jacob B Porrello, Enzo R Akhtar, Mohammed M Jager, Joanna Ashworth, Michael Syrris, Petros Elliott, David A Monserrat, Lorenzo Elliott, Perry M |
author_sort | Lopes, Luis R |
collection | PubMed |
description | AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS : In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS : Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype. |
format | Online Article Text |
id | pubmed-8380059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-83800592021-08-23 Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy Lopes, Luis R Garcia-Hernández, Soledad Lorenzini, Massimiliano Futema, Marta Chumakova, Olga Zateyshchikov, Dmitry Isidoro-Garcia, Maria Villacorta, Eduardo Escobar-Lopez, Luis Garcia-Pavia, Pablo Bilbao, Raquel Dobarro, David Sandin-Fuentes, Maria Catalli, Claudio Gener Querol, Blanca Mezcua, Ainhoa Garcia Pinilla, Jose Bloch Rasmussen, Torsten Ferreira-Aguar, Ana Revilla-Martí, Pablo Basurte Elorz, Maria Teresa Bautista Paves, Alicia Ramon Gimeno, Juan Figueroa, Ana Virginia Franco-Gutierrez, Raul Fuentes-Cañamero, Maria Eugenia Martinez Moreno, Marina Ortiz-Genga, Martin Piqueras-Flores, Jesus Analia Ramos, Karina Rudzitis, Ainars Ruiz-Guerrero, Luis Stein, Ricardo Triguero-Bocharán, Mayte de la Higuera, Luis Ochoa, Juan Pablo Abu-Bonsrah, Dad Kwok, Cecilia Y T Smith, Jacob B Porrello, Enzo R Akhtar, Mohammed M Jager, Joanna Ashworth, Michael Syrris, Petros Elliott, David A Monserrat, Lorenzo Elliott, Perry M Eur Heart J Clinical Research AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS : In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS : Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype. Oxford University Press 2021-07-15 /pmc/articles/PMC8380059/ /pubmed/34263907 http://dx.doi.org/10.1093/eurheartj/ehab424 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Clinical Research Lopes, Luis R Garcia-Hernández, Soledad Lorenzini, Massimiliano Futema, Marta Chumakova, Olga Zateyshchikov, Dmitry Isidoro-Garcia, Maria Villacorta, Eduardo Escobar-Lopez, Luis Garcia-Pavia, Pablo Bilbao, Raquel Dobarro, David Sandin-Fuentes, Maria Catalli, Claudio Gener Querol, Blanca Mezcua, Ainhoa Garcia Pinilla, Jose Bloch Rasmussen, Torsten Ferreira-Aguar, Ana Revilla-Martí, Pablo Basurte Elorz, Maria Teresa Bautista Paves, Alicia Ramon Gimeno, Juan Figueroa, Ana Virginia Franco-Gutierrez, Raul Fuentes-Cañamero, Maria Eugenia Martinez Moreno, Marina Ortiz-Genga, Martin Piqueras-Flores, Jesus Analia Ramos, Karina Rudzitis, Ainars Ruiz-Guerrero, Luis Stein, Ricardo Triguero-Bocharán, Mayte de la Higuera, Luis Ochoa, Juan Pablo Abu-Bonsrah, Dad Kwok, Cecilia Y T Smith, Jacob B Porrello, Enzo R Akhtar, Mohammed M Jager, Joanna Ashworth, Michael Syrris, Petros Elliott, David A Monserrat, Lorenzo Elliott, Perry M Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy |
title | Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy |
title_full | Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy |
title_fullStr | Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy |
title_full_unstemmed | Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy |
title_short | Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy |
title_sort | alpha-protein kinase 3 (alpk3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy |
topic | Clinical Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380059/ https://www.ncbi.nlm.nih.gov/pubmed/34263907 http://dx.doi.org/10.1093/eurheartj/ehab424 |
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