Abstract
Phospholamban, encoded by the PLN gene, is a regulator of intracellular Ca2+. Pathogenic PLN variants cause cardiac remodeling and early death. It is plausible that PLN variants confer a pro-arrhythmic phenotype without overt structural remodeling. To date, most PLN variants associated with sudden cardiac arrest/death (SCA/D) are accompanied by structural cardiomyopathies. The prevalence of PLN variants in autopsy-negative SCA/D cases without overt cardiomyopathy is unclear. We present a case series of patients with PLN gene variants identified due to SCA/D without overt dilated or arrhythmogenic cardiomyopathies. We describe PLN gene variants presenting with primarily arrhythmic phenotypes. The PLN gene should be strongly considered in genetic testing strategies for SCA/D. Cases were ascertained through professional collaboration among cardiovascular genetic counselors. We prioritized cases with PLN variants presenting without recognized cardiomyopathy phenotypes and/or in autopsy-negative SCA/D. We describe five cases with pathogenic PLN variants. Two are previously reported (p.Arg14del, p.Leu39Ter), and one is novel (p.Gln22LeufsX19). There were 3 pediatric cases and 2 adult cases, and 2/3 pediatric cases presented with SCD and negative autopsies. The other pediatric case survived SCA, but follow-up cardiac investigations were normal. Four of five cases had uninformative cardiac phenotypes, though one case had some evidence of cardiac hypertrophy at autopsy. Interestingly, 4/5 cases had SCA/D occur during rest, and 1/5 cases occurred with some activity. Last, one adult with SCD had a history atrial fibrillation, though no other cases had known arrhythmias. Table 1 summarizes these findings for comparison and contrast. With a role in Ca2+ regulation, it is plausible that PLN variants confer a pro-arrhythmic substrate and increased of SCA/D in the absence of cardiomyopathy. We raise awareness for the possible role of PLN variants in phenotype- and autopsy-negative SCA/D and encourage further investigation. This may help guide genetic counseling for PLN variants found in patients at autopsy and/or in patients who have not yet developed cardiomyopathy.
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