Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN: c.40_42delAGA Carriers

Esteban A. Lopera-Maya; Shuang Li; Remco de Brouwer; Ilja M. Nolte; Justin van Breen; Laurens P. Bosman; LifeLines Cohort Study; Tom E. Verstraelen; Freya H. M. van Lint; Moniek G. P. J. Cox; Judith A. Groeneweg; Thomas P. Mast; Paul A. van der Zwaag; Paul G. A. Volders; Reinder Evertz; Lisa Wong; Natasja M. S. de Groot; Katja Zeppenfeld; Jeroen F. van der Heijden; Maarten P. van den Berg; Arthur A. M. Wilde; Folkert W. Asselbergs; Richard N. W. Hauer; Anneline S. J. M. te Riele; J. Peter van Tintelen; Raul Aguirre-Gamboa; Jan A. Kuivenhoven; Esteban A. Lopera Maya; Peter M. Visscher; Judith M. Vonk; Jan D. H. Jongbloed; Morris A. Swertz; Lude Franke; Cisca Wijmenga; Rudolf A. de Boer; Patrick Deelen; Paul A. van der Zwaag; The Netherlands A. C. M./P. L. N. Registry; Serena Sanna

doi:https://doi.org/10.1007/s12265-022-10347-5

Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN: c.40_42delAGA Carriers

Esteban A. Lopera-Maya, Shuang Li, Remco de Brouwer, Ilja M. Nolte, Justin van Breen, Laurens P. Bosman, LifeLines Cohort Study, Tom E. Verstraelen, Freya H. M. van Lint, Moniek G. P. J. Cox, Judith A. Groeneweg, Thomas P. Mast, Paul A. van der Zwaag, Paul G. A. Volders, Reinder Evertz, Lisa Wong, Natasja M. S. de Groot, Katja Zeppenfeld, Jeroen F. van der Heijden, Maarten P. van den BergArthur A. M. Wilde, Folkert W. Asselbergs, Richard N. W. Hauer, Anneline S. J. M. te Riele, J. Peter van Tintelen, Raul Aguirre-Gamboa, Jan A. Kuivenhoven, Esteban A. Lopera Maya, Peter M. Visscher, Judith M. Vonk, Jan D. H. Jongbloed, Morris A. Swertz, Lude Franke, Cisca Wijmenga, Rudolf A. de Boer, Patrick Deelen, Paul A. van der Zwaag, The Netherlands A. C. M./P. L. N. Registry, Serena Sanna

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

Abstract

The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, there are carriers who remain asymptomatic at older ages. To understand the mechanisms behind this incomplete penetrance, we evaluated potential phenotypic and genetic modifiers in 74 PLN:c.40_42delAGA carriers identified in 36,339 participants of the Lifelines population cohort. Asymptomatic carriers (N = 48) showed shorter QRS duration (− 5.73 ms, q value = 0.001) compared to asymptomatic non-carriers, an effect we could replicate in two different independent cohorts. Furthermore, symptomatic carriers showed a higher correlation (rPearson = 0.17) between polygenic predisposition to higher QRS (PGSQRS) and QRS (p value = 1.98 × 10–8), suggesting that the effect of the genetic variation on cardiac rhythm might be increased in symptomatic carriers. Our results allow for improved clinical interpretation for asymptomatic carriers, while our approach could guide future studies on genetic diseases with incomplete penetrance. Graphical abstract: [Figure not available: see fulltext.].

Original language	English
Pages (from-to)	1251-1266
Number of pages	16
Journal	Journal of cardiovascular translational research
Volume	16
Issue number	6
Early online date	2023
DOIs	https://doi.org/10.1007/s12265-022-10347-5
Publication status	Published - Dec 2023

Keywords

Cardiomyopathy
Genome-wide association study
Incomplete penetrance
Modifiers of Mendelian disorders
Polygenic score

Access to Document

https://doi.org/10.1007/s12265-022-10347-5

Cite this

Lopera-Maya, E. A., Li, S., de Brouwer, R., Nolte, I. M., van Breen, J., Bosman, L. P., LifeLines Cohort Study, Verstraelen, T. E., van Lint, F. H. M., Cox, M. G. P. J., Groeneweg, J. A., Mast, T. P., van der Zwaag, P. A., Volders, P. G. A., Evertz, R., Wong, L., de Groot, N. M. S., Zeppenfeld, K., van der Heijden, J. F., ... Sanna, S. (2023). Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN: c.40_42delAGA Carriers. Journal of cardiovascular translational research, 16(6), 1251-1266. https://doi.org/10.1007/s12265-022-10347-5

@article{a6fb6356ac9947c5b597a7348461eb32,

title = "Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN: c.40_42delAGA Carriers",

abstract = "The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, there are carriers who remain asymptomatic at older ages. To understand the mechanisms behind this incomplete penetrance, we evaluated potential phenotypic and genetic modifiers in 74 PLN:c.40_42delAGA carriers identified in 36,339 participants of the Lifelines population cohort. Asymptomatic carriers (N = 48) showed shorter QRS duration (− 5.73 ms, q value = 0.001) compared to asymptomatic non-carriers, an effect we could replicate in two different independent cohorts. Furthermore, symptomatic carriers showed a higher correlation (rPearson = 0.17) between polygenic predisposition to higher QRS (PGSQRS) and QRS (p value = 1.98 × 10–8), suggesting that the effect of the genetic variation on cardiac rhythm might be increased in symptomatic carriers. Our results allow for improved clinical interpretation for asymptomatic carriers, while our approach could guide future studies on genetic diseases with incomplete penetrance. Graphical abstract: [Figure not available: see fulltext.].",

keywords = "Cardiomyopathy, Genome-wide association study, Incomplete penetrance, Modifiers of Mendelian disorders, Polygenic score",

author = "Lopera-Maya, {Esteban A.} and Shuang Li and {de Brouwer}, Remco and Nolte, {Ilja M.} and {van Breen}, Justin and Bosman, {Laurens P.} and {LifeLines Cohort Study} and Verstraelen, {Tom E.} and {van Lint}, {Freya H. M.} and Cox, {Moniek G. P. J.} and Groeneweg, {Judith A.} and Mast, {Thomas P.} and {van der Zwaag}, {Paul A.} and Volders, {Paul G. A.} and Reinder Evertz and Lisa Wong and {de Groot}, {Natasja M. S.} and Katja Zeppenfeld and {van der Heijden}, {Jeroen F.} and {van den Berg}, {Maarten P.} and Wilde, {Arthur A. M.} and Asselbergs, {Folkert W.} and Hauer, {Richard N. W.} and {te Riele}, {Anneline S. J. M.} and {van Tintelen}, {J. Peter} and Raul Aguirre-Gamboa and Kuivenhoven, {Jan A.} and Maya, {Esteban A. Lopera} and Visscher, {Peter M.} and Vonk, {Judith M.} and Jongbloed, {Jan D. H.} and Swertz, {Morris A.} and Lude Franke and Cisca Wijmenga and {de Boer}, {Rudolf A.} and Patrick Deelen and {van der Zwaag}, {Paul A.} and {The Netherlands A. C. M./P. L. N. Registry} and Serena Sanna",

note = "Funding Information: This study was supported by UMCG HAP grant CD017.0031/ronde 2017–2/nr324 (P.vdZ), NWO VIDI grant number 917.164.455 (M.A.S), ERC advanced grant ERC-671274 (C.W.), NWO gravitation grant The Netherlands Organ-on-Chip Initiative 024.003.001 (C.W.) and Spinoza award NWOSPI 92–266 (C.W.), Colciencias fellowship ed.783 (E.A.L.M.), the Netherlands Heart Foundation (2017–21; 2017–11; 2018–30; 2020B005) (R.A.d.B. & R.d.B), the European Research Council (ERC CoG 818715) (R.A.d.B. & R.d.B), and Foundation leDucq (Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN) (R.A.d.B. & R.d.B). Funding Information: The Lifelines Biobank initiative has been made possible by funding from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen (UMCG, Netherlands), University of Groningen and the Northern Provinces of the Netherlands (Drenthe, Friesland, and Groningen). This project was carried out under Lifelines project number OV18_0473. The generation and management of GWAS genotype data for the Lifelines Cohort Study are supported by the UMCG Genetics Lifelines Initiative (UGLI). UGLI is partly supported by a Spinoza Grant from NWO, awarded to Cisca Wijmenga. Funding Information: The authors wish to gratefully acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines, and all the study participants. The Lifelines Biobank initiative has been made possible by funding from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen (UMCG, Netherlands), University of Groningen and the Northern Provinces of the Netherlands (Drenthe, Friesland, and Groningen). This project was carried out under Lifelines project number OV18_0473. The generation and management of GWAS genotype data for the Lifelines Cohort Study are supported by the UMCG Genetics Lifelines Initiative (UGLI). UGLI is partly supported by a Spinoza Grant from NWO, awarded to Cisca Wijmenga. We thank Raul Aguirre-Gamboa for his contribution in informatics training and initial analyses, Mathieu Plateel and Jody Geelderloos-Arends for their contribution in genotyping the Lifelines samples, Kate Mc Intyre for help developing the manuscript and the UMCG Genomics Coordination Center, and the UG Center for Information Technology and their sponsors (BBMRI-NL and TarGet) for storage and computational infrastructure. Lifelines Cohort Study-UGLI Group Authors Raul Aguirre-Gamboa1, Patrick Deelen1, Lude Franke1, Jan A Kuivenhoven2, Esteban A Lopera Maya1, Ilja M Nolte3, Serena Sanna1, Harold Snieder3, Morris A Swertz1, Peter M. Visscher3,4, Judith M Vonk3, Cisca Wijmenga.11University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands.2University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, Netherlands.3University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, Netherlands.4Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. Netherlands ACM/PLN Registry Authors Laurens P Bosman1, Tom E Verstraelen2, Freya HM van Lint3, Moniek GPJ Cox4, Judith A Groeneweg5, Thomas P Mast5, Paul A. van der Zwaag6, Paul GA Volders6, Reinder Evertz8, Lisa Wong9, Natasja MS de Groot10, Katja Zeppenfeld11, Jeroen F van der Heijden5, Maarten P van den Berg4, Arthur AM Wilde2, Folkert W Asselbergs1, Richard NW Hauer1, Anneline SJM te Riele12, J Peter van Tintelen.121Durrer Centre for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands.2Department of Clinical and Experimental Cardiology, Amsterdam UMC, Amsterdam, Netherlands.3Department of Clinical Genetics, Amsterdam UMC, Amsterdam, Netherlands.4Department of Cardiology, UMC Groningen, Groningen, Netherlands.5Department of Cardiology, UMC Utrecht, Utrecht, Netherlands.6Department of Genetics, UMC Groningen, Groningen, Netherlands.7Department of Cardiology, Maastricht UMC, Maastricht, Netherlands.8Department of Cardiology, Radboud MC, Nijmegen, Netherlands.9Department of Cardiology, Amsterdam UMC, Amsterdam, Netherlands.10Department of Cardiology, Erasmus MC, Rotterdam, Netherlands.11Department of Cardiology, LUMC, Leiden, Netherlands.12Durrer Centre for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands. Netherlands ACM/PLN Registry Collaborators A. Amin (Amsterdam UMC, Amsterdam, Netherlands); F.W. Asselbergs (UMC Utrecht, Utrecht, Netherlands); D.Q.C.M. Barge-Schaapveld (LUMC, Leiden, Netherlands); M.P. van den Berg (UMC Groningen, Groningen, Netherlands); S.M. Boekholdt (Amsterdam UMC, Amsterdam, Netherlands); L.P. Bosman (UMC Utrecht, Utrecht, Netherlands); M.G.P.J. Cox (UMC Groningen, Groningen, Netherlands); D. Dooijes (UMC Utrecht, Utrecht, Netherlands); R.N.W. Hauer (Netherlands Heart Institute); A.C. Houweling (Amsterdam UMC, Amsterdam, Netherlands); N.M.S. de Groot (Erasmus MC, Rotterdam, Netherlands); A.S.J.M. te Riele (UMC Utrecht, Utrecht, Netherlands); J.P. van Tintelen (UMC Utrecht, Utrecht, Netherlands); T.E. Verstraelen (Amsterdam UMC, Amsterdam, Netherlands); P.G.A. Volders (MUMC + , Maastricht, Netherlands); A.A.M. Wilde (Amsterdam UMC, Amsterdam, Netherlands); S.C. Yap (Erasmus MC, Rotterdam, Netherlands); K. Zeppenfeld (LUMC, Leiden, Netherlands). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "https://doi.org/10.1007/s12265-022-10347-5",

language = "English",

volume = "16",

pages = "1251--1266",

journal = "Journal of cardiovascular translational research",

issn = "1937-5387",

publisher = "Springer New York",

number = "6",

}

Lopera-Maya, EA, Li, S, de Brouwer, R, Nolte, IM, van Breen, J, Bosman, LP, LifeLines Cohort Study, Verstraelen, TE , van Lint, FHM, Cox, MGPJ, Groeneweg, JA, Mast, TP, van der Zwaag, PA, Volders, PGA, Evertz, R, Wong, L, de Groot, NMS, Zeppenfeld, K, van der Heijden, JF, van den Berg, MP, Wilde, AAM , Asselbergs, FW, Hauer, RNW, te Riele, ASJM, van Tintelen, JP, Aguirre-Gamboa, R, Kuivenhoven, JA, Maya, EAL, Visscher, PM, Vonk, JM, Jongbloed, JDH, Swertz, MA, Franke, L, Wijmenga, C, de Boer, RA, Deelen, P, van der Zwaag, PA, The Netherlands A. C. M./P. L. N. Registry & Sanna, S 2023, 'Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN: c.40_42delAGA Carriers', Journal of cardiovascular translational research, vol. 16, no. 6, pp. 1251-1266. https://doi.org/10.1007/s12265-022-10347-5

TY - JOUR

T1 - Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN

T2 - c.40_42delAGA Carriers

AU - Lopera-Maya, Esteban A.

AU - Li, Shuang

AU - de Brouwer, Remco

AU - Nolte, Ilja M.

AU - van Breen, Justin

AU - Bosman, Laurens P.

AU - LifeLines Cohort Study

AU - Verstraelen, Tom E.

AU - van Lint, Freya H. M.

AU - Cox, Moniek G. P. J.

AU - Groeneweg, Judith A.

AU - Mast, Thomas P.

AU - van der Zwaag, Paul A.

AU - Volders, Paul G. A.

AU - Evertz, Reinder

AU - Wong, Lisa

AU - de Groot, Natasja M. S.

AU - Zeppenfeld, Katja

AU - van der Heijden, Jeroen F.

AU - van den Berg, Maarten P.

AU - Wilde, Arthur A. M.

AU - Asselbergs, Folkert W.

AU - Hauer, Richard N. W.

AU - te Riele, Anneline S. J. M.

AU - van Tintelen, J. Peter

AU - Aguirre-Gamboa, Raul

AU - Kuivenhoven, Jan A.

AU - Maya, Esteban A. Lopera

AU - Visscher, Peter M.

AU - Vonk, Judith M.

AU - Jongbloed, Jan D. H.

AU - Swertz, Morris A.

AU - Franke, Lude

AU - Wijmenga, Cisca

AU - de Boer, Rudolf A.

AU - Deelen, Patrick

AU - van der Zwaag, Paul A.

AU - The Netherlands A. C. M./P. L. N. Registry

AU - Sanna, Serena

N1 - Funding Information: This study was supported by UMCG HAP grant CD017.0031/ronde 2017–2/nr324 (P.vdZ), NWO VIDI grant number 917.164.455 (M.A.S), ERC advanced grant ERC-671274 (C.W.), NWO gravitation grant The Netherlands Organ-on-Chip Initiative 024.003.001 (C.W.) and Spinoza award NWOSPI 92–266 (C.W.), Colciencias fellowship ed.783 (E.A.L.M.), the Netherlands Heart Foundation (2017–21; 2017–11; 2018–30; 2020B005) (R.A.d.B. & R.d.B), the European Research Council (ERC CoG 818715) (R.A.d.B. & R.d.B), and Foundation leDucq (Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN) (R.A.d.B. & R.d.B). Funding Information: The Lifelines Biobank initiative has been made possible by funding from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen (UMCG, Netherlands), University of Groningen and the Northern Provinces of the Netherlands (Drenthe, Friesland, and Groningen). This project was carried out under Lifelines project number OV18_0473. The generation and management of GWAS genotype data for the Lifelines Cohort Study are supported by the UMCG Genetics Lifelines Initiative (UGLI). UGLI is partly supported by a Spinoza Grant from NWO, awarded to Cisca Wijmenga. Funding Information: The authors wish to gratefully acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines, and all the study participants. The Lifelines Biobank initiative has been made possible by funding from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen (UMCG, Netherlands), University of Groningen and the Northern Provinces of the Netherlands (Drenthe, Friesland, and Groningen). This project was carried out under Lifelines project number OV18_0473. The generation and management of GWAS genotype data for the Lifelines Cohort Study are supported by the UMCG Genetics Lifelines Initiative (UGLI). UGLI is partly supported by a Spinoza Grant from NWO, awarded to Cisca Wijmenga. We thank Raul Aguirre-Gamboa for his contribution in informatics training and initial analyses, Mathieu Plateel and Jody Geelderloos-Arends for their contribution in genotyping the Lifelines samples, Kate Mc Intyre for help developing the manuscript and the UMCG Genomics Coordination Center, and the UG Center for Information Technology and their sponsors (BBMRI-NL and TarGet) for storage and computational infrastructure. Lifelines Cohort Study-UGLI Group Authors Raul Aguirre-Gamboa1, Patrick Deelen1, Lude Franke1, Jan A Kuivenhoven2, Esteban A Lopera Maya1, Ilja M Nolte3, Serena Sanna1, Harold Snieder3, Morris A Swertz1, Peter M. Visscher3,4, Judith M Vonk3, Cisca Wijmenga.11University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands.2University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, Netherlands.3University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, Netherlands.4Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. Netherlands ACM/PLN Registry Authors Laurens P Bosman1, Tom E Verstraelen2, Freya HM van Lint3, Moniek GPJ Cox4, Judith A Groeneweg5, Thomas P Mast5, Paul A. van der Zwaag6, Paul GA Volders6, Reinder Evertz8, Lisa Wong9, Natasja MS de Groot10, Katja Zeppenfeld11, Jeroen F van der Heijden5, Maarten P van den Berg4, Arthur AM Wilde2, Folkert W Asselbergs1, Richard NW Hauer1, Anneline SJM te Riele12, J Peter van Tintelen.121Durrer Centre for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands.2Department of Clinical and Experimental Cardiology, Amsterdam UMC, Amsterdam, Netherlands.3Department of Clinical Genetics, Amsterdam UMC, Amsterdam, Netherlands.4Department of Cardiology, UMC Groningen, Groningen, Netherlands.5Department of Cardiology, UMC Utrecht, Utrecht, Netherlands.6Department of Genetics, UMC Groningen, Groningen, Netherlands.7Department of Cardiology, Maastricht UMC, Maastricht, Netherlands.8Department of Cardiology, Radboud MC, Nijmegen, Netherlands.9Department of Cardiology, Amsterdam UMC, Amsterdam, Netherlands.10Department of Cardiology, Erasmus MC, Rotterdam, Netherlands.11Department of Cardiology, LUMC, Leiden, Netherlands.12Durrer Centre for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Netherlands. Netherlands ACM/PLN Registry Collaborators A. Amin (Amsterdam UMC, Amsterdam, Netherlands); F.W. Asselbergs (UMC Utrecht, Utrecht, Netherlands); D.Q.C.M. Barge-Schaapveld (LUMC, Leiden, Netherlands); M.P. van den Berg (UMC Groningen, Groningen, Netherlands); S.M. Boekholdt (Amsterdam UMC, Amsterdam, Netherlands); L.P. Bosman (UMC Utrecht, Utrecht, Netherlands); M.G.P.J. Cox (UMC Groningen, Groningen, Netherlands); D. Dooijes (UMC Utrecht, Utrecht, Netherlands); R.N.W. Hauer (Netherlands Heart Institute); A.C. Houweling (Amsterdam UMC, Amsterdam, Netherlands); N.M.S. de Groot (Erasmus MC, Rotterdam, Netherlands); A.S.J.M. te Riele (UMC Utrecht, Utrecht, Netherlands); J.P. van Tintelen (UMC Utrecht, Utrecht, Netherlands); T.E. Verstraelen (Amsterdam UMC, Amsterdam, Netherlands); P.G.A. Volders (MUMC + , Maastricht, Netherlands); A.A.M. Wilde (Amsterdam UMC, Amsterdam, Netherlands); S.C. Yap (Erasmus MC, Rotterdam, Netherlands); K. Zeppenfeld (LUMC, Leiden, Netherlands). Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, there are carriers who remain asymptomatic at older ages. To understand the mechanisms behind this incomplete penetrance, we evaluated potential phenotypic and genetic modifiers in 74 PLN:c.40_42delAGA carriers identified in 36,339 participants of the Lifelines population cohort. Asymptomatic carriers (N = 48) showed shorter QRS duration (− 5.73 ms, q value = 0.001) compared to asymptomatic non-carriers, an effect we could replicate in two different independent cohorts. Furthermore, symptomatic carriers showed a higher correlation (rPearson = 0.17) between polygenic predisposition to higher QRS (PGSQRS) and QRS (p value = 1.98 × 10–8), suggesting that the effect of the genetic variation on cardiac rhythm might be increased in symptomatic carriers. Our results allow for improved clinical interpretation for asymptomatic carriers, while our approach could guide future studies on genetic diseases with incomplete penetrance. Graphical abstract: [Figure not available: see fulltext.].

AB - The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, there are carriers who remain asymptomatic at older ages. To understand the mechanisms behind this incomplete penetrance, we evaluated potential phenotypic and genetic modifiers in 74 PLN:c.40_42delAGA carriers identified in 36,339 participants of the Lifelines population cohort. Asymptomatic carriers (N = 48) showed shorter QRS duration (− 5.73 ms, q value = 0.001) compared to asymptomatic non-carriers, an effect we could replicate in two different independent cohorts. Furthermore, symptomatic carriers showed a higher correlation (rPearson = 0.17) between polygenic predisposition to higher QRS (PGSQRS) and QRS (p value = 1.98 × 10–8), suggesting that the effect of the genetic variation on cardiac rhythm might be increased in symptomatic carriers. Our results allow for improved clinical interpretation for asymptomatic carriers, while our approach could guide future studies on genetic diseases with incomplete penetrance. Graphical abstract: [Figure not available: see fulltext.].

KW - Cardiomyopathy

KW - Genome-wide association study

KW - Incomplete penetrance

KW - Modifiers of Mendelian disorders

KW - Polygenic score

UR - http://www.scopus.com/inward/record.url?scp=85159886304&partnerID=8YFLogxK

U2 - https://doi.org/10.1007/s12265-022-10347-5

DO - https://doi.org/10.1007/s12265-022-10347-5

M3 - Article

C2 - 36622581

SN - 1937-5387

VL - 16

SP - 1251

EP - 1266

JO - Journal of cardiovascular translational research

JF - Journal of cardiovascular translational research

IS - 6

ER -

Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN: c.40_42delAGA Carriers

Abstract

Keywords

Access to Document

Other files and links

Cite this