Key result
Asymptomatic carriers of the PLN c.40_42delAGA variant had a significantly shorter QRS duration (-5.73 ms) compared to asymptomatic non-carriers, a finding replicated in independent cohorts.
Why the study?
While the PLN c.40_42delAGA variant causes dilated and arrhythmogenic cardiomyopathy, some carriers remain asymptomatic or show mild symptoms in old age, and the mechanisms behind this incomplete penetrance were not understood.
Observational (n=36,339)
Yes
Shorter QRS duration is associated with the absence of cardiomyopathy symptoms in PLN c.40_42delAGA carriers, suggesting it may serve as a protective phenotypic marker.
Answers are grounded in this paper and cite their sources.
Shorter QRS may aid risk stratification in asymptomatic PLN carriers; hypothesis-generating for polygenic modifiers of incomplete penetrance.
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, other carriers remain asymptomatic or show only mild symptoms in old age. 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, p-value=0.001) compared to asymptomatic non-carriers and symptomatic carriers (N=26), and we replicated this in different subset of 21,771 participants from the Lifelines cohort (−3.87 ms, p-value=0.028) and in 592 carriers from the Arrhythmogenic Cardiomyopathy (ACM) patient registry (−6.91 ms, p-value=0.0002). Furthermore, symptomatic carriers showed a higher correlation between genetic predisposition to higher QRS duration (PGS QRS ) and QRS (p-value=1.98×10 -8 ), suggesting that symptomatic PLN c.40_42delAGA carriers may have an increased sensitivity to the effect of genetic variation in cardiac rhythm. Our results may help improve risk prediction models for cardiac outcomes for future studies, while our approach could guide studies on genetic diseases with incomplete penetrance.
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Lopera-Maya et al. (2022) conducted an observational in PLN c.40_42delAGA variant carriers (cardiomyopathy risk) (n=36,339). Asymptomatic PLN c.40_42delAGA carrier status vs. Asymptomatic non-carriers was evaluated on QRS duration (MD -5.73 ms, 95% CI -9.22 to -2.24, p=0.001). Asymptomatic carriers of the PLN c.40_42delAGA variant had a significantly shorter QRS duration (-5.73 ms) compared to asymptomatic non-carriers, a finding replicated in independent cohorts.
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