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Desmosomal Mutations in Dilated Cardiomyopathy.

Dilated cardiomyopathy, (DCM), is a heart muscle disease characterised by unexplained dilatation of the left ventricle, impaired systolic function and histological abnormalities dominated by myocardial fibrosis. The condition has an estimated prevalence of 1:2.500 and is a frequent cause of heart failure and cardiac transplantation in the young (1-3). Patients may experience severe disease complications including thromboembolic events and sudden death due to malignant arrhythmias.
Myocardial Disease

The aetiology of DCM is poorly understood and appears to be very heterogeneous. Viral infections, autoimmune disease and toxic substances are believed to be causative in a proportion of DCM although definitive proof has often been difficult to obtain. Recent studies have suggested that DCM has a familial appearance in 30-50% of cases implying that genetic factors may play an important role in disease development in a substantial proportion of patients (3). More than 40 disease genes have been identified encoding proteins involved in a variety of cell functions ranging from force generation within the sarcomere to regulation of ion-channels. Most affected families present with a “pure” cardiac phenotype and in these families autosomal dominant transmission is most frequent followed by recessive and X-linked inheritance. Recent studies have suggested a particular severe disease expression in DCM patients carrying mutations in the gene for lamin A/C, encoding a nuclear enveloped protein, expressed in most human cells.

In the paper of the month the authors report the frequency of desmosomal protein gene mutations in a cohort of 100 unrelated DCM probands. Previous studies have identified mutations in the same genes in patients with arrythmogenic right ventricle cardiomyopathy, (ARVC), which is a condition characterised by dilatation of the right ventricle, development of myocardial aneurysms, ventricular arrhythmias, and fibro-fatty replacement of myocytes. Since some ARVC patients present with biventricular disease the authors hypothesized that desmosomal gene mutations may also be associated with DCM (4). All patients in the current study fulfilled diagnostic criteria of DCM without any signs of ARVC. Five mutations were identified in 5 probands in addition to sequence variants of uncertain pathogenic significance in an additional
13 probands. Relatives were available for clinical and genetic investigations in 2 families in which a total of 6 mutation carriers presented with a heterogeneous disease expression.

This paper is the first to report that desmosomal gene mutations are responsible for a significant proportion of DCM and not only restricted to be the causative agent in ARVC. The results illustrate that genetic investigations have provided important knowledge about the aetiology of hereditary cardiac conditions and underscores that mutations in the same gene may lead to a variety of different cardiac conditions and manifestations. In addition to the disease associated mutations reported a fairly large number of sequence variations within the genes investigated were identified. However due to the limited number of affected individuals available for the study it was not possible to establish if these variations were disease associated which illustrates the difficulties in how to interpret the results of the genetic investigations. The authors rightfully argue that a conservative approach is preferable and that additional affected individuals carrying identical mutations should be available before sequence variants should be used for genetic counselling.


The paper illustrates some of the challenges we are facing in genetic diagnosis of hereditary conditions in the years to come not least due to the rapid development in gene technology. Next Generation Sequencing, (NGS), platforms have been developed enabling large-scale genotyping of many disease genes, very quickly and at low costs (5;6). The amount of data created by NGS is tremendous and skilful staff in bioinformatics is required with powerful computers to investigate which sequence variants are likely to be disease associated and may have an impact on disease expression. In this context the establishment of European registers gathering genotype-phenotype information is becoming increasingly important in order to provide solid evidence of whether sequence variations are likely to be disease associated or not. Such registers will contribute to create a more solid basis for counselling affected families in the future.


Circ Cardiovasc Genet. 2010;3:314-22

  1. Mestroni,L., Maisch,B., McKenna,W.J., Schwartz,K., Charron,P., Rocco,C., Tesson,F., Richter,A., Wilke,A., and Komajda,M. 1999. Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur.Heart J. 20:93-102.

  2. Towbin,J.A. and Bowles,N.E. 2000. The failing heart. Nature 415:227-233.

  3. Mahon N.G., Murphy R.T., MacRae C.A., Caforio A.L., Elliott P.M., McKenna W.J. 2005. Echocardiographic evaluation in asymptomatic relatives of patients with dilated cardiomyopathy reveals preclinical disease. Ann Intern Med. 19:108-15.

  4. Norman M., Simpson M., Mogensen J., Shaw A., Hughes S., Syrris P., Chowdhry S.S., Rowland E., Crosby A., McKenna W.J. 2005. A Novel Mutation in Desmoplakin causes Arrythmogenic Left Ventricular Cardiomyopathy. Circulation:112, 636-42.

  5. Choi,M., Scholl,U.I., Ji,W., Liu,T., Tikhonova,I.R., Zumbo,P., Nayir,A., Bakkaloglu,A., Ozen,S., Sanjad,S. et al. 2009. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc.Natl.Acad.Sci.U.S.A. 106:19096-19101.

  6. Ng,S.B., Buckingham,K.J., Lee,C., Bigham,A.W., Tabor,H.K., Dent,K.M., Huff,C.D., Shannon,P.T., Jabs,E.W., Nickerson,D.A. et al. 2010. Exome sequencing identifies the cause of a mendelian disorder. Nat.Genet.2010. 42:30-35.

Notes to editor

Presented by:
Dr Torsten B Rasmussen, Dr Tenna Gadgaard & Dr Jens Mogensen,
Department of Cardiology, Aarhus University Hospital, Skejby, Denmark
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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