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. 2010 Feb 9;55(6):587-97.
doi: 10.1016/j.jacc.2009.11.020.

Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy

Tianhong Xu  1 , Zhao Yang, Matteo Vatta, Alessandra Rampazzo, Giorgia Beffagna, Kalliopi Pilichou, Steven E Scherer, Jeffrey Saffitz, Joshua Kravitz, Wojciech Zareba, Gian Antonio Danieli, Alessandra Lorenzon, Andrea Nava, Barbara Bauce, Gaetano Thiene, Cristina Basso, Hugh Calkins, Kathy Gear, Frank Marcus, Jeffrey A Towbin; Multidisciplinary Study of Right Ventricular Dysplasia Investigators
Affiliations

Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy

Tianhong Xu et al. J Am Coll Cardiol. .

Erratum in

  • J Am Coll Cardiol. 2010 Mar 30;55(13):1401. Pillichou, Kalliopi [corrected to Pilichou, Kalliopi]

Abstract

Objectives: The aim of this study was to define the genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC).

Background: Arrhythmogenic right ventricular cardiomyopathy, characterized by right ventricular fibrofatty replacement and arrhythmias, causes sudden death. Autosomal dominant inheritance, reduced penetrance, and 7 desmosome-encoding causative genes are known. The basis of low penetrance is poorly understood.

Methods: Arrhythmogenic right ventricular cardiomyopathy probands and family members were enrolled, blood was obtained, lymphoblastoid cell lines were immortalized, deoxyribonucleic acid was extracted, polymerase chain reaction (PCR) amplification of desmosome-encoding genes was performed, PCR products were sequenced, and diseased tissue samples were studied for intercellular junction protein distribution with confocal immunofluorescence microscopy and antibodies against key proteins.

Results: We identified 21 variants in plakophilin-2 (PKP2) in 38 of 198 probands (19%), including missense, nonsense, splice site, and deletion/insertion mutations. Pedigrees showed wide intra-familial variability (severe early-onset disease to asymptomatic individuals). In 9 of 38 probands, PKP2 variants were identified that were encoded in trans (compound heterozygosity). The 38 probands hosting PKP2 variants were screened for other desmosomal genes mutations; second variants (digenic heterozygosity) were identified in 16 of 38 subjects with PKP2 variants (42%), including desmoplakin (DSP) (n = 6), desmoglein-2 (DSG2) (n = 5), plakophilin-4 (PKP4) (n = 1), and desmocollin-2 (DSC2) (n = 1). Heterozygous mutations in non-PKP 2 desmosomal genes occurred in 14 of 198 subjects (7%), including DSP (n = 4), DSG2 (n = 5), DSC2 (n = 3), and junctional plakoglobin (JUP) (n = 2). All variants occurred in conserved regions; none was identified in 700 ethnic-matched control subjects. Immunohistochemical analysis demonstrated abnormalities of protein architecture.

Conclusions: These data suggest that the genetic basis of ARVC includes reduced penetrance with compound and digenic heterozygosity. Disturbed junctional cytoarchitecture in subjects with desmosomal mutations confirms that ARVC is a disease of the desmosome and cell junction.

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Figures

Figure 1
Figure 1. Pedigrees of three families with PKP2 variants and incomplete penetrance
Panel A: L404fsX409 PKP2 was identified in the proband and unaffected sister and was inherited from the unaffected mother (+; in blue). In addition, a de novo variant, DSP Q90R, was identified in the proband (◆). The arrow indicates the proband. Panel B: K456NfsX458 was identified in the proband and inherited from the unaffected mother (+). The arrow indicates the proband. NA: Not available for genetic analysis. Panel C: Pedigree of a family with compound heterozygous PKP2 variants. V837fsX930 (+) was identified in the proband and both of his siblings and was inherited from the unaffected father, who in turn inherited it from his unaffected father. R388W (◆) was identified in the proband and his affected brother and was inherited from his phenotypically normal mother. The arrow indicates the proband. NA: Not available for genetic analysis.
Figure 1
Figure 1. Pedigrees of three families with PKP2 variants and incomplete penetrance
Panel A: L404fsX409 PKP2 was identified in the proband and unaffected sister and was inherited from the unaffected mother (+; in blue). In addition, a de novo variant, DSP Q90R, was identified in the proband (◆). The arrow indicates the proband. Panel B: K456NfsX458 was identified in the proband and inherited from the unaffected mother (+). The arrow indicates the proband. NA: Not available for genetic analysis. Panel C: Pedigree of a family with compound heterozygous PKP2 variants. V837fsX930 (+) was identified in the proband and both of his siblings and was inherited from the unaffected father, who in turn inherited it from his unaffected father. R388W (◆) was identified in the proband and his affected brother and was inherited from his phenotypically normal mother. The arrow indicates the proband. NA: Not available for genetic analysis.
Figure 2
Figure 2. Pedigree of two U.S. families with compound desmosomal mutations (digenic heterozygosity)
Panel A: PKP2 I531S (+) was identified in the proband and two of her siblings. DSP W207X (◆) was identified in the proband who experienced sudden death at 25 years of age. Her affected living brother was diagnosed by cardiac MRI and is still alive at the age of 42 years. Her unaffected sister carrying the I531S variant is now 51years of age and has twin unaffected daughters, aged 19 years, both of whom carry the variant. Individuals without a definitive diagnosis of ARVC, but in whom signs or symptoms compatible with this diagnosis were reported, are identified in blue. The arrow indicates the proband. Panel B: PKP2 S140F (+), PKP2 IVS10-1G>C (◆) and DSG2 V56M (♣) were detected in the proband. The oldest child of the proband, who is 19 years old, does not meet full Task Force criteria of ARVC but has arrhythmias and symptoms. The arrow indicates the proband. SD: Sudden death; ABN Echo: Abnormal echocardiogram; CHF: Congestive Heart Failure; PM: Pacemaker
Figure 2
Figure 2. Pedigree of two U.S. families with compound desmosomal mutations (digenic heterozygosity)
Panel A: PKP2 I531S (+) was identified in the proband and two of her siblings. DSP W207X (◆) was identified in the proband who experienced sudden death at 25 years of age. Her affected living brother was diagnosed by cardiac MRI and is still alive at the age of 42 years. Her unaffected sister carrying the I531S variant is now 51years of age and has twin unaffected daughters, aged 19 years, both of whom carry the variant. Individuals without a definitive diagnosis of ARVC, but in whom signs or symptoms compatible with this diagnosis were reported, are identified in blue. The arrow indicates the proband. Panel B: PKP2 S140F (+), PKP2 IVS10-1G>C (◆) and DSG2 V56M (♣) were detected in the proband. The oldest child of the proband, who is 19 years old, does not meet full Task Force criteria of ARVC but has arrhythmias and symptoms. The arrow indicates the proband. SD: Sudden death; ABN Echo: Abnormal echocardiogram; CHF: Congestive Heart Failure; PM: Pacemaker
Figure 3
Figure 3. Pedigree of two Italian families with compound desmosomal mutations
Panel A: PKP2 T816fsX825 (◆) was identified in the proband and two family members. PKP2 S209R (+) and DSG2 R146H (♣) were also identified in the proband. Panel B: PKP2 Q211X (+), PKP2 I778T (♣) and DSP R1255K (◆) were detected in the proband. All family members carrying different mutations were completely asymptomatic. The probands are indicated by the arrows. SD: Sudden death; aSD: aborted sudden death.
Figure 3
Figure 3. Pedigree of two Italian families with compound desmosomal mutations
Panel A: PKP2 T816fsX825 (◆) was identified in the proband and two family members. PKP2 S209R (+) and DSG2 R146H (♣) were also identified in the proband. Panel B: PKP2 Q211X (+), PKP2 I778T (♣) and DSP R1255K (◆) were detected in the proband. All family members carrying different mutations were completely asymptomatic. The probands are indicated by the arrows. SD: Sudden death; aSD: aborted sudden death.
Figure 4
Figure 4. Immunostaining of myocardial sections from a control heart and from the hearts of ARVC patients PG (PKP2 W538X) and M686 (PKP2 I531S and DSP W207X)
The panels show staining for PKP2 (top), DSP (middle), and CX43 (bottom). Bars = 20μm
See this image and copyright information in PMC

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