TY - JOUR
T1 - Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN:c.40_42delAGA Carriers
AU - Maya, Esteban A.Lopera
AU - Li, Shuang
AU - de Brouwer, Remco
AU - Nolte, Ilja M.
AU - van Breen, Justin
AU - Bosman, Laurens P.
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 - Sanna, Serena
N1 - 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 - https://www.scopus.com/pages/publications/85159886304
U2 - 10.1007/s12265-022-10347-5
DO - 10.1007/s12265-022-10347-5
M3 - Article
C2 - 36622581
AN - SCOPUS:85159886304
SN - 1937-5387
VL - 16
SP - 1251
EP - 1266
JO - Journal of Cardiovascular Translational Research
JF - Journal of Cardiovascular Translational Research
IS - 6
ER -