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 dis...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) |
| Repositorio: | r-FISABIO. Repositorio Institucional de Producción Científica |
| OAI Identifier: | oai:fisabio.fundanetsuite.com:p11798 |
| Acceso en línea: | https://fisabio.portalinvestigacion.com/publicaciones/11798 |
| Access Level: | acceso abierto |
| Palabra clave: | ALPK3 Hypertrophic cardiomyopathy Genetics |
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Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathyLopes, LRGarcia-Hernandez, SLorenzini, MFutema, MChumakova, OZateyshchikov, DIsidoro-Garcia, MVillacorta, EEscobar-Lopez, LGarcia-Pavia, PBilbao, RDobarro, DSandin-Fuentes, MCatalli, CQuerol, BGMezcua, APinilla, JGRasmussen, TBFerreira-Aguar, ARevilla-Marti, PElorz, MTBPaves, ABGimeno, JRFigueroa, AVFranco-Gutierrez, RFuentes-Canamero, MEMoreno, MMOrtiz-Genga, MPiqueras-Flores, JRamos, KARudzitis, ARuiz-Guerrero, LStein, RTriguero-Bocharan, Mde la Higuera, LOchoa, JPAbu-Bonsrah, DKwok, CYTSmith, JBPorrello, ERAkhtar, MMJager, JAshworth, MSyrris, PElliott, DAMonserrat, LElliott, PMALPK3Hypertrophic cardiomyopathyGeneticsAims 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 apicaUconcentric 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 +/- 5.7years, 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. [GRAPHICS] .OXFORD UNIV PRESS2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/11798EUROPEAN HEART JOURNALISSN: 0195668XISSNe: 15229645reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)Inglésinfo:eu-repo/semantics/openAccessoai:fisabio.fundanetsuite.com:p117982026-06-11T12:45:17Z |
| dc.title.none.fl_str_mv |
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 |
| spellingShingle |
Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy Lopes, LR ALPK3 Hypertrophic cardiomyopathy Genetics |
| title_short |
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_sort |
Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy |
| dc.creator.none.fl_str_mv |
Lopes, LR Garcia-Hernandez, S Lorenzini, M Futema, M Chumakova, O Zateyshchikov, D Isidoro-Garcia, M Villacorta, E Escobar-Lopez, L Garcia-Pavia, P Bilbao, R Dobarro, D Sandin-Fuentes, M Catalli, C Querol, BG Mezcua, A Pinilla, JG Rasmussen, TB Ferreira-Aguar, A Revilla-Marti, P Elorz, MTB Paves, AB Gimeno, JR Figueroa, AV Franco-Gutierrez, R Fuentes-Canamero, ME Moreno, MM Ortiz-Genga, M Piqueras-Flores, J Ramos, KA Rudzitis, A Ruiz-Guerrero, L Stein, R Triguero-Bocharan, M de la Higuera, L Ochoa, JP Abu-Bonsrah, D Kwok, CYT Smith, JB Porrello, ER Akhtar, MM Jager, J Ashworth, M Syrris, P Elliott, DA Monserrat, L Elliott, PM |
| author |
Lopes, LR |
| author_facet |
Lopes, LR Garcia-Hernandez, S Lorenzini, M Futema, M Chumakova, O Zateyshchikov, D Isidoro-Garcia, M Villacorta, E Escobar-Lopez, L Garcia-Pavia, P Bilbao, R Dobarro, D Sandin-Fuentes, M Catalli, C Querol, BG Mezcua, A Pinilla, JG Rasmussen, TB Ferreira-Aguar, A Revilla-Marti, P Elorz, MTB Paves, AB Gimeno, JR Figueroa, AV Franco-Gutierrez, R Fuentes-Canamero, ME Moreno, MM Ortiz-Genga, M Piqueras-Flores, J Ramos, KA Rudzitis, A Ruiz-Guerrero, L Stein, R Triguero-Bocharan, M de la Higuera, L Ochoa, JP Abu-Bonsrah, D Kwok, CYT Smith, JB Porrello, ER Akhtar, MM Jager, J Ashworth, M Syrris, P Elliott, DA Monserrat, L Elliott, PM |
| author_role |
author |
| author2 |
Garcia-Hernandez, S Lorenzini, M Futema, M Chumakova, O Zateyshchikov, D Isidoro-Garcia, M Villacorta, E Escobar-Lopez, L Garcia-Pavia, P Bilbao, R Dobarro, D Sandin-Fuentes, M Catalli, C Querol, BG Mezcua, A Pinilla, JG Rasmussen, TB Ferreira-Aguar, A Revilla-Marti, P Elorz, MTB Paves, AB Gimeno, JR Figueroa, AV Franco-Gutierrez, R Fuentes-Canamero, ME Moreno, MM Ortiz-Genga, M Piqueras-Flores, J Ramos, KA Rudzitis, A Ruiz-Guerrero, L Stein, R Triguero-Bocharan, M de la Higuera, L Ochoa, JP Abu-Bonsrah, D Kwok, CYT Smith, JB Porrello, ER Akhtar, MM Jager, J Ashworth, M Syrris, P Elliott, DA Monserrat, L Elliott, PM |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
ALPK3 Hypertrophic cardiomyopathy Genetics |
| topic |
ALPK3 Hypertrophic cardiomyopathy Genetics |
| 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 apicaUconcentric 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 +/- 5.7years, 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. [GRAPHICS] . |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://fisabio.portalinvestigacion.com/publicaciones/11798 |
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https://fisabio.portalinvestigacion.com/publicaciones/11798 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
| dc.publisher.none.fl_str_mv |
OXFORD UNIV PRESS |
| publisher.none.fl_str_mv |
OXFORD UNIV PRESS |
| dc.source.none.fl_str_mv |
EUROPEAN HEART JOURNAL ISSN: 0195668X ISSNe: 15229645 reponame:r-FISABIO. Repositorio Institucional de Producción Científica instname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) |
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Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) |
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r-FISABIO. Repositorio Institucional de Producción Científica |
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r-FISABIO. Repositorio Institucional de Producción Científica |
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1869403641426739200 |
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15,812429 |