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Arrhythmogenic Right Ventricular Cardiomyopathy With Recessive Inheritance Related to a New Homozygous Desmocollin-2 Mutation
Canadian Journal of Cardiology
-
(2014) 1.e1e1.e3 www.onlinecjc.ca
Case Report
Arrhythmogenic Right Ventricular Cardiomyopathy With Recessive Inheritance Related to a New Homozygous Desmocollin-2 Mutation Basil Al-Sabeq, MD,a Andrew D. Krahn, MD, FRCPC,b Susan Conacher, MSc,a George J. Klein, MD, FRCPC,a and Zachary Laksman, MD, FRCPCa a b
Division of Cardiology, Department of Medicine, University of Western Ontario, London, Ontario, Canada
Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
ABSTRACT
RESUM E
Arrhythmogenic right ventricular cardiomyopathy/dysplasia is an inherited cardiomyopathy that is transmitted in autosomal dominant and autosomal recessive forms and involves mutations in desmosomal and extradesmosomal genes. We present a case of arrhythmogenic right ventricular cardiomyopathy that cosegregates in a Lebanese family with a previously unreported desmocollin-2 mutation (c.712_714delGAT). We believe this newly described genetic variant displays autosomal recessive inheritance without the cutaneous manifestations expected in recessive genotypes, and represents the latest addition to the compendium of desmosomal mutations with pathogenic potential.
La cardiomyopathie ou dysplasie arythmogène du ventricule droit est re ditaire qui est transmise dans les formes une cardiomyopathie he cessives et les formes autosomiques dominantes, et autosomiques re qui cause les mutations des gènes desmosomals et extrasentons un cas de cardiomyopathie arythmodesmosomals. Nous pre gre ge e dans une famille gène du ventricule droit qui s’est cose te libanaise ayant une mutation de la desmocolline-2 qui n’avait pas e e ante rieurement (c.712_714delGAT). Nous croyons que ce rapporte ne tique re cemment de crit montre une transmission autovariant ge cessive sans les manifestations cutane es auxquelles nous somique re sence de ge notypes re cessifs, et repre sente le nous attendons en pre dernier ajout au compendium des mutations desmosomales ayant un potentiel pathogène.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of myocardial tissue, right ventricular dilation and reduced function, and a propensity toward ventricular arrhythmias and sudden cardiac death. ARVC is typically inherited in an autosomal dominant fashion, with culprit mutations most often found in the 5 desmosomal genes.1 Autosomal recessive variations with mutations in plakoglobin (JUP, Naxos disease) and desmoplakin (DSP, Carvajal syndrome) are well documented and invariably involve palmoplantar keratoderma and woolly hair phenotypes. We report a novel and putatively pathogenic desmocollin (DSC)-2 mutation in a patient with cardiac-restricted ARVC.
Case Description A 10-year-old girl suffered a witnessed, exercise-induced sudden cardiac arrest. Electrocardiography demonstrated a right bundle branch block and diffuse T-wave inversions. Transthoracic echocardiography and cardiac magnetic resonance imaging revealed a dilated, hypokinetic right ventricle with moderately reduced function and a focal area of dyskinesis. Telemetry showed frequent ventricular ectopy with left bundle branch block and superior axis. The patient had a secundum atrial septal defect closure and pulmonary valvuloplasty at the age of 2 years. She had no skin or hair abnormalities. She had no family history of sudden cardiac death, and there is no known consanguinity between her parents, whose familial roots lie in small, adjacent Lebanese villages. Further investigations included an endomyocardial biopsy that displayed subendocardial fibrosis, and genetic testing that revealed a homozygous trinucleotide deletion in DSC2 (exon 6: c.712_714delGAT, p.Asp238del, National Center for Biotechnology Information reference sequence NC_000018.9) (GeneDx, Gaithersburg, MD). Cascade screening was
Received for publication November 15, 2013. Accepted January 21, 2014. Corresponding author: Dr Zachary Laksman, Division of Cardiology, Department of Medicine, University of Western Ontario, 339 Windermere Rd, London, Ontario N6A 5A5, Canada. E-mail: [email protected] See page 1.e2 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2014.01.014
1.e2
performed on the proband’s parents and siblings (2 brothers) (Supplemental Table S1). The proband met a definite diagnosis of ARVC according to the revised 2010 Task Force criteria, and all screened relatives harboured a single variant of the DSC2 mutation, but were clinically unaffected (Fig. 1, Supplemental Table S1). An implantable cardioverter-defibrillator was inserted. Over the subsequent 5 years, the index patient has been clinically well. Her electrocardiogram (Fig. 2A) and signal-averaged electrocardiogram (Supplemental Fig. S1) continued to have features compatible with ARVC. She has received 1 appropriate shock during an episode of exertional syncope (Fig. 2B). Discussion Our case demonstrates typical and advanced features of ARVC with a homozygous DSC2 mutation that corresponds to an in-frame deletion of an aspartic acid residue. This residue is highly conserved across species and previously unreported as either a benign polymorphism or disease-causing mutation in the literature. This contrasts with previously reported disease-causing DSC2 mutations, in which single base deletions or substitutions2 resulted in premature termination codons and truncated protein products. Moreover, a genetic precedent has not been set by large-scale exome sequence databases,3 which lack ethnically-matched control subjects for our case and do not contain variants with single DSC2 in-frame amino acid deletions.
Canadian Journal of Cardiology Volume - 2014
Notwithstanding, we believe the mutation described represents a pathogenic autosomal recessive form of ARVC as suggested by in silico analysis (PROVEAN Protein, J. Craig Venter Institute, San Diego, CA) (Supplemental Fig. S2). This deletion, involving the extracellular cadherin 1 domain, is predicted to impart a deleterious effect with high specificity.4 Cosegregation of the condition in a nuclear family with phenotypically silent heterozygous carriers has also been demonstrated. Although limited by a paucity of genetic testing in extended family members, and without homozygosity mapping, the lack of affected family members across several generations argues against a dominant mode of transmission. A common syndrome linking our patient’s congenital heart disease and ARVC could potentially be at play, or might have independent genetic substrates. Our case complements a recent study2 suggesting recessive ARVC without cutaneous traits in a North American Hutterite population with a homozygous founder mutation in DSC2. The lack of skin and hair abnormalities in both reports might be accounted for by alternate isoforms of DSC (DSC1, DSC3) expressed in the integument but not cardiac tissue, with DSC1 restricted to the epidermis.5 Our findings highlight the growing body of evidence surrounding the heterogeneity of the genetic basis of ARVC and its genotype-phenotype correlation. Disclosures The authors have no conflicts of interest to disclose. References 1. Rickelt S, Pieperhoff S. Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases. Cell Tissue Res 2012;348:325-33. 2. Gerull B, Kirchner F, Chong JX, et al. Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population. Circ Cardiovasc Genet 2013;6:327-36. 3. NHLBI Exome Sequencing Project (ESP). Exome Variant Server. Available at: http://evs.gs.washington.edu/EVS. Accessed December 19, 2013. 4. Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PLoS One 2012;7: e46688. 5. Nuber UA, Schäfer S, Schmidt A, Koch PJ, Franke WW. The widespread human desmocollin Dsc2 and tissue-specific patterns of synthesis of various desmocollin subtypes. Eur J Cell Biol 1995;66:69-74.
Figure 1. Pedigree of proband (arrow) and nuclear family for desmocollin-2 mutation c.712_714delGAT. Age (in years) and mutation status are indicated as follows: white ¼ unaffected; black ¼ affected; -/- ¼ homozygous for the aforementioned mutation; þ/- ¼ heterozygous for the aforementioned mutation.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2014.01.014.
Al-Sabeq et al. ARVC Related to Homozygous DSC-2 Mutation
1.e3
Figure 2. (A) Abnormal 12-lead electrocardiogram displaying sinus bradycardia with diffuse T-wave inversions, left axis deviation, right bundle branch block pattern, and epsilon waves, consistent with arrhythmogenic right ventricular cardiomyopathy. (B) Intracardiac tracing from implantable cardioverter defibrillator demonstrating monomorphic ventricular tachycardia that quickly becomes polymorphic and degenerates into ventricular fibrillation. This was successfully treated with a 34.7 J shock (not shown).
-
(2014) 1.e1e1.e3 www.onlinecjc.ca
Case Report
Arrhythmogenic Right Ventricular Cardiomyopathy With Recessive Inheritance Related to a New Homozygous Desmocollin-2 Mutation Basil Al-Sabeq, MD,a Andrew D. Krahn, MD, FRCPC,b Susan Conacher, MSc,a George J. Klein, MD, FRCPC,a and Zachary Laksman, MD, FRCPCa a b
Division of Cardiology, Department of Medicine, University of Western Ontario, London, Ontario, Canada
Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
ABSTRACT
RESUM E
Arrhythmogenic right ventricular cardiomyopathy/dysplasia is an inherited cardiomyopathy that is transmitted in autosomal dominant and autosomal recessive forms and involves mutations in desmosomal and extradesmosomal genes. We present a case of arrhythmogenic right ventricular cardiomyopathy that cosegregates in a Lebanese family with a previously unreported desmocollin-2 mutation (c.712_714delGAT). We believe this newly described genetic variant displays autosomal recessive inheritance without the cutaneous manifestations expected in recessive genotypes, and represents the latest addition to the compendium of desmosomal mutations with pathogenic potential.
La cardiomyopathie ou dysplasie arythmogène du ventricule droit est re ditaire qui est transmise dans les formes une cardiomyopathie he cessives et les formes autosomiques dominantes, et autosomiques re qui cause les mutations des gènes desmosomals et extrasentons un cas de cardiomyopathie arythmodesmosomals. Nous pre gre ge e dans une famille gène du ventricule droit qui s’est cose te libanaise ayant une mutation de la desmocolline-2 qui n’avait pas e e ante rieurement (c.712_714delGAT). Nous croyons que ce rapporte ne tique re cemment de crit montre une transmission autovariant ge cessive sans les manifestations cutane es auxquelles nous somique re sence de ge notypes re cessifs, et repre sente le nous attendons en pre dernier ajout au compendium des mutations desmosomales ayant un potentiel pathogène.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of myocardial tissue, right ventricular dilation and reduced function, and a propensity toward ventricular arrhythmias and sudden cardiac death. ARVC is typically inherited in an autosomal dominant fashion, with culprit mutations most often found in the 5 desmosomal genes.1 Autosomal recessive variations with mutations in plakoglobin (JUP, Naxos disease) and desmoplakin (DSP, Carvajal syndrome) are well documented and invariably involve palmoplantar keratoderma and woolly hair phenotypes. We report a novel and putatively pathogenic desmocollin (DSC)-2 mutation in a patient with cardiac-restricted ARVC.
Case Description A 10-year-old girl suffered a witnessed, exercise-induced sudden cardiac arrest. Electrocardiography demonstrated a right bundle branch block and diffuse T-wave inversions. Transthoracic echocardiography and cardiac magnetic resonance imaging revealed a dilated, hypokinetic right ventricle with moderately reduced function and a focal area of dyskinesis. Telemetry showed frequent ventricular ectopy with left bundle branch block and superior axis. The patient had a secundum atrial septal defect closure and pulmonary valvuloplasty at the age of 2 years. She had no skin or hair abnormalities. She had no family history of sudden cardiac death, and there is no known consanguinity between her parents, whose familial roots lie in small, adjacent Lebanese villages. Further investigations included an endomyocardial biopsy that displayed subendocardial fibrosis, and genetic testing that revealed a homozygous trinucleotide deletion in DSC2 (exon 6: c.712_714delGAT, p.Asp238del, National Center for Biotechnology Information reference sequence NC_000018.9) (GeneDx, Gaithersburg, MD). Cascade screening was
Received for publication November 15, 2013. Accepted January 21, 2014. Corresponding author: Dr Zachary Laksman, Division of Cardiology, Department of Medicine, University of Western Ontario, 339 Windermere Rd, London, Ontario N6A 5A5, Canada. E-mail: [email protected] See page 1.e2 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2014.01.014
1.e2
performed on the proband’s parents and siblings (2 brothers) (Supplemental Table S1). The proband met a definite diagnosis of ARVC according to the revised 2010 Task Force criteria, and all screened relatives harboured a single variant of the DSC2 mutation, but were clinically unaffected (Fig. 1, Supplemental Table S1). An implantable cardioverter-defibrillator was inserted. Over the subsequent 5 years, the index patient has been clinically well. Her electrocardiogram (Fig. 2A) and signal-averaged electrocardiogram (Supplemental Fig. S1) continued to have features compatible with ARVC. She has received 1 appropriate shock during an episode of exertional syncope (Fig. 2B). Discussion Our case demonstrates typical and advanced features of ARVC with a homozygous DSC2 mutation that corresponds to an in-frame deletion of an aspartic acid residue. This residue is highly conserved across species and previously unreported as either a benign polymorphism or disease-causing mutation in the literature. This contrasts with previously reported disease-causing DSC2 mutations, in which single base deletions or substitutions2 resulted in premature termination codons and truncated protein products. Moreover, a genetic precedent has not been set by large-scale exome sequence databases,3 which lack ethnically-matched control subjects for our case and do not contain variants with single DSC2 in-frame amino acid deletions.
Canadian Journal of Cardiology Volume - 2014
Notwithstanding, we believe the mutation described represents a pathogenic autosomal recessive form of ARVC as suggested by in silico analysis (PROVEAN Protein, J. Craig Venter Institute, San Diego, CA) (Supplemental Fig. S2). This deletion, involving the extracellular cadherin 1 domain, is predicted to impart a deleterious effect with high specificity.4 Cosegregation of the condition in a nuclear family with phenotypically silent heterozygous carriers has also been demonstrated. Although limited by a paucity of genetic testing in extended family members, and without homozygosity mapping, the lack of affected family members across several generations argues against a dominant mode of transmission. A common syndrome linking our patient’s congenital heart disease and ARVC could potentially be at play, or might have independent genetic substrates. Our case complements a recent study2 suggesting recessive ARVC without cutaneous traits in a North American Hutterite population with a homozygous founder mutation in DSC2. The lack of skin and hair abnormalities in both reports might be accounted for by alternate isoforms of DSC (DSC1, DSC3) expressed in the integument but not cardiac tissue, with DSC1 restricted to the epidermis.5 Our findings highlight the growing body of evidence surrounding the heterogeneity of the genetic basis of ARVC and its genotype-phenotype correlation. Disclosures The authors have no conflicts of interest to disclose. References 1. Rickelt S, Pieperhoff S. Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases. Cell Tissue Res 2012;348:325-33. 2. Gerull B, Kirchner F, Chong JX, et al. Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population. Circ Cardiovasc Genet 2013;6:327-36. 3. NHLBI Exome Sequencing Project (ESP). Exome Variant Server. Available at: http://evs.gs.washington.edu/EVS. Accessed December 19, 2013. 4. Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PLoS One 2012;7: e46688. 5. Nuber UA, Schäfer S, Schmidt A, Koch PJ, Franke WW. The widespread human desmocollin Dsc2 and tissue-specific patterns of synthesis of various desmocollin subtypes. Eur J Cell Biol 1995;66:69-74.
Figure 1. Pedigree of proband (arrow) and nuclear family for desmocollin-2 mutation c.712_714delGAT. Age (in years) and mutation status are indicated as follows: white ¼ unaffected; black ¼ affected; -/- ¼ homozygous for the aforementioned mutation; þ/- ¼ heterozygous for the aforementioned mutation.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2014.01.014.
Al-Sabeq et al. ARVC Related to Homozygous DSC-2 Mutation
1.e3
Figure 2. (A) Abnormal 12-lead electrocardiogram displaying sinus bradycardia with diffuse T-wave inversions, left axis deviation, right bundle branch block pattern, and epsilon waves, consistent with arrhythmogenic right ventricular cardiomyopathy. (B) Intracardiac tracing from implantable cardioverter defibrillator demonstrating monomorphic ventricular tachycardia that quickly becomes polymorphic and degenerates into ventricular fibrillation. This was successfully treated with a 34.7 J shock (not shown).