PKP2 – Dilated Cardiomyopathy

Several genetic studies have investigated the role of PKP2 in dilated cardiomyopathy (DCM) but yield conflicting results. In a large Dutch family with left‐dominant arrhythmogenic cardiomyopathy, the PKP2 variant c.419C>T (p.Ser140Phe) was identified in three unaffected carriers and failed to cosegregate with disease (PMID:23270881). A prospective cohort of 10 407 individuals, including 2 688 who developed heart failure or arrhythmias, found c.419C>T in 98 carriers (0.94%) with no significant association with DCM (OR 0.72, P≥0.05) or heart failure outcomes (PMID:26264440). Targeted sequencing in DCM case series and diagnostic panels similarly did not reveal PKP2 truncating or missense variants enriched in DCM patients. In vitro assays of p.Ser140Phe demonstrated normal PKP2 localization and unaltered desmosomal function. Collectively, the genetic and functional evidence does not support a causal link between PKP2 variation—particularly c.419C>T—and DCM.

Key Take-home: Current data dispute PKP2 as a primary DCM gene, highlighting the need for gene‐specific validation before clinical reporting.

References

• Heart Rhythm • 2013 • Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype? PMID:23270881
• European Journal of Human Genetics • 2016 • Plakophilin-2 c.419C>T and risk of heart failure and arrhythmias in the general population. PMID:26264440

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