Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
BMC Medical Genetics
Published in: BMC Medical Genetics 1/2017

Open Access 01-12-2017 | Case report

Case reports of two pedigrees with recessive arrhythmogenic right ventricular cardiomyopathy associated with homozygous Thr335Ala variant in DSG2

Authors: Sami Qadri, Olli Anttonen, Juho Viikilä, Eija H. Seppälä, Samuel Myllykangas, Tero-Pekka Alastalo, Miia Holmström, Tiina Heliö, Juha W. Koskenvuo

Published in: BMC Medical Genetics | Issue 1/2017

Login to get access

Abstract

Background

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics.

Case presentation

We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c.1003A > G, p.(Thr335Ala) was discovered in the index patients using next-generation sequencing panels. The presence of this variant in probands’ siblings and children was studied by Sanger sequencing. Five homozygotes and nine heterozygotes were found with the mutation. Participants were evaluated clinically where possible, and available medical records were obtained. All patients homozygous for the variant fulfilled the current diagnostic criteria for ARVC, whereas none of the heterozygous subjects had symptoms suggestive of ARVC or other cardiomyopathies.

Conclusions

The homozygous DSG2 variant c.1003A > G co-segregated with ARVC, indicating autosomal recessive inheritance and complete penetrance. More research is needed to establish a detailed understanding of the relevance of rare variants in ARVC associated genes, which is essential for informative genetic counseling and rational family member testing.
Appendix
Available only for authorised users
Literature
1.
Basso C, Bauce B, Corrado D, Thiene G. Pathophysiology of arrhythmogenic cardiomyopathy. Nat Rev Cardiol. 2012;9:223–33.CrossRef
2.
Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, et al. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982;65:384–98.CrossRefPubMed
3.
Nava A, Thiene G, Canciani B, Scognamiglio R, Daliento L, Buja G, et al. Familial occurrence of right ventricular dysplasia: a study involving nine families. J Am Coll Cardiol. 1988;12:1222–8.CrossRefPubMed
4.
Corrado D, Basso C, Thiene G, McKenna WJ, Davies MJ, Fontaliran F, et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol. 1997;30:1512–20.CrossRefPubMed
5.
Sen-Chowdhry S, Syrris P, Prasad SK, Hughes SE, Merrifield R, Ward D, et al. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. J Am Coll Cardiol. 2008;52:2175–87.CrossRefPubMed
6.
Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med. 1988;318:129–33.CrossRefPubMed
7.
Corrado D, Thiene G, Nava A, Rossi L, Pennelli N. Sudden death in young competitive athletes: clinicopathologic correlations in 22 cases. Am J Med. 1990;89:588–96.CrossRefPubMed
8.
Virmani R, Burke AP, Farb A, Kark JA. Causes of sudden death in young and middle-aged competitive athletes. Cardiol Clin. 1997;15:439–66.CrossRefPubMed
9.
Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010;121:1533–41.CrossRefPubMedPubMedCentral
10.
Rampazzo A, Nava A, Danieli GA, Buja G, Daliento L, Fasoli G, et al. The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23-q24. Hum Mol Genet. 1994;3:959–62.CrossRefPubMed
11.
Peters S, Trümmel M, Meyners W. Prevalence of right ventricular dysplasia-cardiomyopathy in a non-referral hospital. Int J Cardiol. 2004;97:499–501.CrossRefPubMed
12.
Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of right ventricular cardiomyopathy. J Cardiovasc Electrophysiol. 2005;16:927–35.CrossRefPubMed
13.
Campuzano O, Alcalde M, Allegue C, Iglesias A, Garcia-Pavia P, Partemi S, et al. Genetics of arrhythmogenic right ventricular cardiomyopathy. J Med Genet. 2013;50:280–9.CrossRefPubMed
14.
Nava A, Scognamiglio R, Thiene G, Canciani B, Daliento L, Buja G, et al. A polymorphic form of familial arrhythmogenic right ventricular dysplasia. Am J Cardiol. 1987;59:1405–9.CrossRefPubMed
15.
Protonotarios N, Tsatsopoulou A, Patsourakos P, Alexopoulos D, Gezerlis P, Simitsis S, et al. Cardiac abnormalities in familial palmoplantar keratosis. Br Heart J. 1986;56:321–6.CrossRefPubMedPubMedCentral
16.
Coonar AS, Protonotarios N, Tsatsopoulou A, Needham EWA, Houlston RS, Cliff S, et al. Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation. 1998;97:2049–58.CrossRefPubMed
17.
Simpson MA, Mansour S, Ahnood D, Kalidas K, Patton MA, McKenna WJ, et al. Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair. Cardiology. 2009;113:28–34.CrossRefPubMed
18.
Al-Sabeq B, Krahn AD, Conacher S, Klein GJ, Laksman Z. Arrhythmogenic right ventricular cardiomyopathy with recessive inheritance related to a new homozygous desmocollin-2 mutation. Can J Cardiol. 2014;30:696. e1-696.e3PubMed
19.
Rasmussen TB, Palmfeldt J, Nissen PH, Magnoni R, Dalager S, Jensen UB, et al. Mutated desmoglein-2 proteins are incorporated into desmosomes and exhibit dominant-negative effects in arrhythmogenic right ventricular cardiomyopathy. Hum Mutat. 2013;34:697–705.CrossRefPubMed
20.
Garcia-Pavia P, Syrris P, Salas C, Evans A, Mirelis JG, Cobo-Marcos M, et al. Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study. Heart. 2011;97:1744–52.CrossRefPubMed
21.
Elliott P, O'Mahony C, Syrris P, Evans A, Rivera Sorensen C, Sheppard MN, et al. Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy. Circ Cardiovasc Genet. 2010;3:314–22.CrossRefPubMed
22.
Akinrinade O, Ollila L, Vattulainen S, Tallila J, Gentile M, Salmenpera P, et al. Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. Eur Heart J. 2015;36:2327–37.CrossRefPubMedPubMedCentral
23.
Bauce B, Nava A, Beffagna G, Basso C, Lorenzon A, Smaniotto G, et al. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2010;7:22–9.CrossRefPubMed
24.
Quarta G, Syrris P, Ashworth M, Jenkins S, Zuborne Alapi K, Morgan J, et al. Mutations in the Lamin a/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2012;33:1128–36.CrossRefPubMed
25.
James CA, Bhonsale A, Tichnell C, Murray B, Russell SD, Tandri H, et al. Exercise increases age-related Penetrance and arrhythmic risk in Arrhythmogenic right ventricular dysplasia/Cardiomyopathy–associated Desmosomal mutation carriers. J Am Coll Cardiol. 2013;62:1290–7.CrossRefPubMed
26.
Xu T, Yang Z, Vatta M, Rampazzo A, Beffagna G, Pilichou K, et al. Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2010;55:587–97.CrossRefPubMedPubMedCentral
27.
Rigato I, Bauce B, Rampazzo A, Zorzi A, Pilichou K, Mazzotti E, et al. Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy. Circ Cardiovasc Genet. 2013;6:533–42.CrossRefPubMed
28.
Bhonsale A, Groeneweg JA, James CA, Dooijes D, Tichnell C, Jongbloed JDH, et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J. 2015;36:847–55.CrossRefPubMed
29.
Pinto YM, Elliott PM, Arbustini E, Adler Y, Anastasakis A, Bohm M, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. 2016;37:1850–8.CrossRefPubMed
30.
Myllykangas S, Buenrostro JD, Natsoulis G, Bell JM, Ji HP. Efficient targeted resequencing of human germline and cancer genomes by oligonucleotide-selective sequencing. Nat Biotechnol. 2011;29:1024–7.CrossRefPubMedPubMedCentral
31.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.CrossRefPubMedPubMedCentral
32.
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.CrossRefPubMed
33.
34.
The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526:68–74.
35.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.CrossRefPubMedPubMedCentral
36.
den Haan AD, Tan BY, Zikusoka MN, Llado LI, Jain R, Daly A, et al. Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. CirculationCardiovascular Genetics. 2009;2:428–35.CrossRef
37.
Tan BY, Jain R, den Haan AD, Chen Y, Dalal D, Tandri H, et al. Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Cardiovasc Transl Res. 2010;3:663–73.CrossRefPubMedPubMedCentral
38.
Christensen AH, Benn M, Bundgaard H, Tybjaerg-Hansen A, Haunso S, Svendsen JH. Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy. J Med Genet. 2010;47:736–44.CrossRefPubMed
39.
Quarta G, Muir A, Pantazis A, Syrris P, Gehmlich K, Garcia-Pavia P, et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation. 2011;123:2701–9.CrossRefPubMed
40.
Cox MG, van der Zwaag PA, van der Werf C, van der Smagt JJ, Noorman M, Bhuiyan ZA, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study. Circulation. 2011;123:2690–700.CrossRefPubMed
41.
Riele T, Anneline SJM, James CA, Philips B, Rastegar N, Bhonsale A, Groeneweg JA, et al. Mutation-positive arrhythmogenic right ventricular dysplasia/cardiomyopathy: the triangle of dysplasia displaced. J Cardiovasc Electrophysiol. 2013;24:1311–20.CrossRef
42.
Bhonsale A, James CA, Tichnell C, Murray B, Madhavan S, Philips B, et al. Risk stratification in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. Circulation: Arrhythmia and Electrophysiology. 2013;6:569–78.
43.
Philips B, Madhavan S, James CA, te Riele AS, Murray B, Tichnell C, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear. Circ Arrhythm Electrophysiol. 2014;7:230–6.CrossRefPubMed
44.
van der Zwaag PA, Jongbloed JDH, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H, et al. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat. 2009;30:1278–83.CrossRefPubMed
45.
Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014;16:601–8.CrossRefPubMed
46.
Posch MG, Posch MJ, Geier C, Erdmann B, Mueller W, Richter A, et al. A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy. Mol Genet Metab. 2008;95:74–80.CrossRefPubMed
47.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRefPubMedPubMedCentral
Metadata
Title
Case reports of two pedigrees with recessive arrhythmogenic right ventricular cardiomyopathy associated with homozygous Thr335Ala variant in DSG2
Authors
Sami Qadri
Olli Anttonen
Juho Viikilä
Eija H. Seppälä
Samuel Myllykangas
Tero-Pekka Alastalo
Miia Holmström
Tiina Heliö
Juha W. Koskenvuo
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2017
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-017-0442-3

Other articles of this Issue 1/2017

BMC Medical Genetics 1/2017 Go to the issue

Research article

The (FTO) gene polymorphism is associated with metabolic syndrome risk in Egyptian females: a case- control study

Research article

Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip

Case report

A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature

Case report

A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis

Research article

A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients

Correction

Correction to: Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report