Genetic modifiers to the PLN L39X mutation in a patient with DCM and sustained ventricular tachycardia

[first paragraph of article] Idiopathic dilated cardiomyopathy (DCM) is a leading cause of heart failure characterized by an enlarged ventricular cavity leading to systolic dysfunction. DCM patients have a considerable annual mortality rate of 5–10%, with half of them being sudden unexpected deaths due to ventricular tachycardia (VT) or ventricular fibrillation (VF). Although a multifactorial disease, DCM appears to be inheritable in approximately 70% of cases. Causative gene mutations have been identified in a broad range of genes coding for proteins with a variety of function, such as cytoskeletal, sarcomeric or ion homeostasis related. Among the latter category, several mutations have been identified in Ca 2+ handling proteins in familial and sporadic DCM cases. An increasing body of evidence indicates that abnormal intracellular Ca 2+ handling underlies contractile dysfunction and contributes to ventricular arrhythmogenesis in failing myocardium. A prime example is phospholamban (PLN), which is directly involved in the uptake of Ca 2+ by the sarcoplasmic reticulum (SR), on a beat-to-beat basis, thereby regulating cardiac contraction and relaxation. PLN mutations have been directly associated with the development of dilated cardiomyopathy and heart failure in patients and animal models. However, modifier genes are thought to influence the clinical outcome both in PLN cases, as well as DCM cases in general. We herein describe a DCM case which illustrates the complex genetic contribution to disease development and progression.