Elsevier

Heart Rhythm

Volume 10, Issue 4, April 2013, Pages 548-559
Heart Rhythm

Left-dominant arrhythmogenic cardiomyopathy in a large family: Associated desmosomal or nondesmosomal genotype?

https://doi.org/10.1016/j.hrthm.2012.12.020Get rights and content

Background

Arrhythmogenic cardiomyopathy (AC) is considered a predominantly right ventricular (RV) desmosomal disease. However, left-dominant forms due to desmosomal gene mutations, including PKP2 variant c.419C>T, have been described. Recently, a nondesmosomal phospholamban (PLN) mutation (c.40_42delAGA) has been identified, causing dilated cardiomyopathy and arrhythmias.

Objective

To gain more insight into pathogenicity of the PKP2 variant c.419C>T by cosegregation analysis of the PKP2 variant c.419C>T vs the PLN mutation c.40_42delAGA.

Methods

A Dutch family (13 family members, median age 49 years, range 34–71 years) with ventricular tachycardia underwent (1) meticulous phenotypic characterization and (2) screening of 5 desmosomal genes (PKP2, DSC2, DSG2, DSP, JUP) and PLN.

Results

Six family members fulfilled 2010 AC Task Force Criteria. Seven had signs of left ventricular (LV) involvement (inverted T waves in leads V4–V6, LV wall motion abnormalities and late enhancement, and reduced LV ejection fraction), including 6 family members with proven AC. The PKP2 variant c.419C>T was found as a single variant in 3 family members, combined with the PLN mutation c.40_42delAGA in 3 others. PLN mutation was found in 9 family members, including the 6 with AC and all 7 with LV involvement. The PLN mutation c.40_42delAGA was found as a single mutation in 6, combined with the PKP2 variant c.419C>T in 3 others. A low-voltage electrocardiogram was seen in 4 of 9 PLN mutation-positive subjects. None of the family members with the single PKP2 variant showed any sign of RV or LV involvement.

Conclusions

The PLN mutation c.40_42delAGA cosegregates with AC and with electrocardiographic and structural LV abnormalities. In this family, there was no evidence of disease-causing contribution of the PKP2 variant c.419C>T.

Introduction

In the classical description, arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is considered a hereditary cardiac disease, characterized by ventricular arrhythmias of right ventricular (RV) origin with fibrofatty replacement of cardiomyocytes, predominantly in the RV.1, 2, 3 More recently, patients and families with ventricular arrhythmia and similar ARVD/C histopathologic changes in the left ventricle (LV) have been recognized and described as left-dominant arrhythmogenic cardiomyopathy.4 Mutations in desmosomal genes are associated with both ARVD/C and left-dominant arrhythmogenic cardiomyopathy and at the molecular level both ventricles and the interventricular septum are similarly affected.5, 6, 7 These considerations suggested the designation “arrhythmogenic cardiomyopathy” (AC) as the preferred terminology.8

Desmosomes are protein complexes located in the intercalated disc, which are important for mechanical integrity.9 Desmosomal dysfunction may give rise to loss of mechanical cell-cell adhesion and leads to downregulation and/or altered distribution of other intercalated disc proteins, that is, gap junction proteins (connexion 43 [Cx43]) and sodium channels (Nav1.5).6, 10 These alterations give rise to electrical cell-cell uncoupling and slow conduction, thereby providing a substrate for early activation delay and thus reentrant ventricular tachyarrhythmia.5, 6, 9, 11, 12, 13, 14, 15, 16, 17 Presumably, at a later stage, myocyte loss and fibrofatty replacement will have a major impact on tissue architecture, giving rise to zigzag conduction pathways and load mismatch, further contributing to enhanced activation delay.5, 14, 15, 16

Pathogenic mutations in 5 known desmosomal genes are related to right, left, and biventricular forms of AC: plakophilin-2 (PKP2), desmoplakin (DSP), plakoglobin (JUP), desmoglein-2 (DSG2), and desmocollin-2 (DSC2).18, 19, 20, 21, 22, 23, 24 In approximately 60% of Dutch patients with AC, a pathogenic desmosomal mutation is found, predominantly truncating mutations in the PKP2 gene.11, 19

The PKP2 variant c.419C>T (p.Ser140Phe) is a missense variant that alters 1 amino acid. It has been reported to be associated with both classical right-sided AC and a left-dominant form in individual patients and in families.4, 20, 25, 26, 27, 28, 29 However, the pathogenicity of this variant is not supported by in silico prediction algorithms Sorting Intolerant from Tolerant and Polymorphism Phenotyping-2.30, 31 No functional tests to assess pathogenicity have been performed thus far.

This report presents a family with monomorphic ventricular tachycardia (VT) with 2 potentially causative mutations: the desmosomal PKP2 variant c.419C>T and a recently identified mutation c.40_42delAGA (p.Arg14del) in the nondesmosomal phospholamban (PLN) gene.32 The PLN gene is involved in calcium homeostasis, and mutation-positive subjects are phenotypically characterized by low-voltage electrocardiograms (ECGs), ventricular arrhythmias, and contractile dysfunction.32, 33, 34, 35

The aim of the study was to gain insight into the pathogenicity of the PKP2 variant c.419C>T vs cosegregation analysis of the PKP2 variant c.419C>T vs the PLN mutation c.40_42delAGA.

Section snippets

Study population

A Dutch family of 4 generations and 30 family members, 13 of whom were available for screening (median age 46 years, range 34–71 years, 4 men), with VT underwent (1) meticulous phenotypic characterization and (2) mutation analysis.

Clinical evaluation

Standard patient evaluation included detailed assessment of clinical and family history, physical examination, and 12-lead ECG (while off drugs). In the presence of cardiac symptoms and/or an abnormal ECG, analysis was extended with 48-hour ambulatory ECG monitoring

Family

At age 51, the index patient (III:8; see pedigree in Figure 1) presented with a monomorphic VT with right bundle branch block morphology, right axis deviation, and cycle length 230 ms. Clinical analysis showed a low-voltage ECG (<0.5 mV in standard leads) and a structurally normal heart on cineangiography and echocardiography with LVEF 62%. At age 63, she presented again with the same VT but remarkably longer cycle length (while off drugs) of 350 ms (Figure 2). By then, the LVEF had

PLN cosegregation and phenotypic characteristics

The PLN mutation c.40_42delAGA cosegregated with AC diagnosis and electrocardiographic and structural LV abnormalities. In this family, mutation-positive subjects were often identified by the presence of low-voltage ECGs. In addition, PLN mutation-positive subjects with AC had RV and LV involvement, negative T waves in leads V4–V6, and wall motion abnormalities and/or DE in the LV.

The c.40_42delAGA (p.Arg14del) mutation results in the deletion of a highly conserved residue and is not or very

Conclusions

A PLN mutation cosegregates with the diagnosis of AC and with electrocardiographic and structural LV abnormalities. Mutation-positive subjects are phenotypically characterized by low voltages and inverted T waves in left precordial leads on the ECG. In this family, there is no evidence of individual disease causing contribution of the single c.419C>T variant in PKP2.

Acknowledgments

We are grateful to the family members for their effort, interest, and cooperation.

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    This study was supported by the Netherlands Heart Foundation (grants 2007B132 and 2007B139), Interuniversity Cardiology Institute of the Netherlands (project 06901), and the Heart Lung Foundation Utrecht (to Dr Groeneweg, Dr Cox, Dr van Veen, and Dr Hauer). Dr McKenna acknowledges a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme.

    The first 2 authors contributed equally to this work.

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