Submission Details

PLN : Intrinsic Cardiomyopathy. The PLN gene is associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (van der Zwaag, 2012 PMID: 22820313) and heart failure of unknown etiology. The typical inheritance for PLN related cardiomyopathy is autosomal dominant, albeit autosomal recessive inheritance has been noted and appears to follow a dosage effect or semidominance, as loss of both alleles results in an earlier and more severe phenotypic presentation (Haghighi, 2003 PMID: 12639993). PLN is encoded by one exon, and missense, nonsense, and frameshift mutations in the coding exon and the promoter region have been reported. Given that PLN only has one exon, many of the mutations (even LOF) result in a protein product. PLN encodes the 52 amino acid protein, phospholamban, that functions to regulate SERCA2 function in the sarcoplasmic reticulum. Phospholamban exists in both monomeric and homopentameric forms. The monomeric form is thought to inhibit SERCA2 activity. PLN-mediated SERCA2 inhibition is released upon phosphorylation of monomeric PLN by either PKA or CAMKII, and thus stabilization of the pentameric form (reviewed in Haghighi, 2014 PMID: 25451386, Young, 2015 PMID: 25563649). While the distinct genetic mechanism of PLN-mediated cardiomyopathy is unclear, the overall disease mechanism for PLN associated cardiomyopathy is dysregulation of SERCA2 function, Ca2+ handling, and disrupted relaxation and contraction of the heart. Multiple cases of PLN-mediated cardiomyopathy are reported in the literature, allowing and extending beyond the maximum score for genetic evidence (12 pts). This gene-disease association is supported by the function of the gene product, alteration of normal function in non-patient cells expressing patient-derived mutant PLN, and animal models. In summary, PLN is definitively associated with intrinsic cardiomyopathy. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Hypertrophic Cardiomyopathy Gene Curation committee on September 19, 2017 using SOP version 4. This gene-disease relationship was updated and recurated on February 12, 2021.

Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) underlying the disease entities: (1) Cardiomyopathy, dilated, 1P (MIM: 609909) and (2) Cardiomyopathy, hypertrophic, 18 (MIM:613874). Evidence suggests that the mechanism of the disease is impaired SERCA2 regulation of Ca2+ handling for all conditions associated with PLN. Furthermore, a progressive cardiomyopathy beginning with hypertrophic and leading to dilated has been observed in a proband (Haghighi, 2003 PMID: 12639993). Both interfamilial and intrafamilial variability were observed between PLN variants (Haghighi, 2003 PMID: 12639993; van der Zwaag, 2012 PMID: 22820313). For clinical management, no striking differences should occur, as all of the phenotypes and conditions associated with PLN are of cardiovascular nature, and individuals should be monitored appropriately. Therefore, all of the disease entities have been lumped into one disease entity, Intrinsic cardiomyopathy.

Data on the occurrence of cardiomyopathy in individuals with PLN associated intrinsic cardiomyopathy was collected by the Hypertrophic Cardiomyopathy Gene Curation Committee (subgroup of the Cardiovascular Working Group). Mutation of PLN results in the development of an intrinsic cardiomyopathy that can present with left ventricular hypertrophy. The mechanism for PLN induced intrinsic cardiomyopathy is attributed to SERCA2 dysfunction and improper Ca2+- handling, which significantly alters contraction and relaxation of the heart, resulting in heart failure (reviewed in Haghighi, 2014 PMID: 25451386, Young, 2015 PMID: 25563649).