Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy

Tianhong Xu, Zhao Yang, Matteo Vatta, Alessandra Rampazzo, Giorgia Beffagna, Kalliopi Pillichou, 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 Towbin

Research output: Contribution to journalArticle

202 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)587-597
Number of pages11
JournalJournal of the American College of Cardiology
Volume55
Issue number6
DOIs
StatePublished - Feb 9 2010
Externally publishedYes

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Plakophilins
Arrhythmogenic Right Ventricular Dysplasia
Desmosomes
Desmoglein 2
Penetrance
Desmocollins
Desmoplakins
Intercellular Junctions
Mutation
Genes
INDEL Mutation
gamma Catenin
Asymptomatic Diseases
Polymerase Chain Reaction
Proteins
Pedigree
Sudden Death
Fluorescence Microscopy
Confocal Microscopy
Cardiac Arrhythmias

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy. / Xu, Tianhong; Yang, Zhao; Vatta, Matteo; Rampazzo, Alessandra; Beffagna, Giorgia; Pillichou, Kalliopi; Scherer, Steven E.; Saffitz, Jeffrey; Kravitz, Joshua; Zareba, Wojciech; Danieli, Gian Antonio; Lorenzon, Alessandra; Nava, Andrea; Bauce, Barbara; Thiene, Gaetano; Basso, Cristina; Calkins, Hugh; Gear, Kathy; Marcus, Frank; Towbin, Jeffrey.

In: Journal of the American College of Cardiology, Vol. 55, No. 6, 09.02.2010, p. 587-597.

Research output: Contribution to journalArticle

Xu, T, Yang, Z, Vatta, M, Rampazzo, A, Beffagna, G, Pillichou, K, Scherer, SE, Saffitz, J, Kravitz, J, Zareba, W, Danieli, GA, Lorenzon, A, Nava, A, Bauce, B, Thiene, G, Basso, C, Calkins, H, Gear, K, Marcus, F & Towbin, J 2010, 'Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy', Journal of the American College of Cardiology, vol. 55, no. 6, pp. 587-597. https://doi.org/10.1016/j.jacc.2009.11.020
Xu, Tianhong ; Yang, Zhao ; Vatta, Matteo ; Rampazzo, Alessandra ; Beffagna, Giorgia ; Pillichou, Kalliopi ; Scherer, Steven E. ; Saffitz, Jeffrey ; Kravitz, Joshua ; Zareba, Wojciech ; Danieli, Gian Antonio ; Lorenzon, Alessandra ; Nava, Andrea ; Bauce, Barbara ; Thiene, Gaetano ; Basso, Cristina ; Calkins, Hugh ; Gear, Kathy ; Marcus, Frank ; Towbin, Jeffrey. / Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy. In: Journal of the American College of Cardiology. 2010 ; Vol. 55, No. 6. pp. 587-597.
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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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T1 - Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy

AU - Xu, Tianhong

AU - Yang, Zhao

AU - Vatta, Matteo

AU - Rampazzo, Alessandra

AU - Beffagna, Giorgia

AU - Pillichou, Kalliopi

AU - Scherer, Steven E.

AU - Saffitz, Jeffrey

AU - Kravitz, Joshua

AU - Zareba, Wojciech

AU - Danieli, Gian Antonio

AU - Lorenzon, Alessandra

AU - Nava, Andrea

AU - Bauce, Barbara

AU - Thiene, Gaetano

AU - Basso, Cristina

AU - Calkins, Hugh

AU - Gear, Kathy

AU - Marcus, Frank

AU - Towbin, Jeffrey

PY - 2010/2/9

Y1 - 2010/2/9

N2 - 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.

AB - 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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