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Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction


Klassen et al. (1) investigated the presence of mutations in 6 sarcomeric protein genes (MYH7, TNNT2, TNNI3, ACTC, MYL2 and MYL3) in 63 index patients with isolated left ventricular noncompaction. They found mutations potentially associated with the development of the disease in 11 probands (17%). Eight had mutations in MYH7, 1 in TNNT2 and 2 had the same mutation in ACTC. They also demonstrated that there was a familial presentation of the disease in 6 of the eleven cases, with ages of presentation between 6 and 70 years.

The authors conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects, and that their findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.

Sarcomeric protein gene mutations may cause left ventricular noncompaction

Recently, several authors have demonstrated that sarcomeric protein gene mutations may cause left ventricular noncompaction (LVNC)(1-3). This interesting paper confirms these previous observations and suggests that sarcomeric gene mutations may be one of the most frequent causes of this phenotype. Moreover we have to bear in mind that the authors have not analysed some of the main sarcomeric genes usually associated with the development of cardiomyopathies, as MYBPC3 (encoding the myosin-binding protein C) or TPM1 (encoding alpha tropomyosin).

Isolated left ventricular noncompaction has been defined as an unclassified cardiomyopathy characterized by the presence of prominent trabeculations and invaginations usually affecting the apical segments of the left ventricule. Different diagnostic criteria have been suggested based in the number and depth of the trabeculations, the thickness of the compact epicardial layer and the absence of associated congenital heart defects. All this criteria have been somehow arbitrarily defined, and have been based in the comparison of the characteristics of patients with severe forms of the disease against healthy controls. As other cardiomyopathies, left ventricular noncompaction is a familial disease that may be secondary to multiple different genetic defects. Familial and genetic studies are showing us the usefulness and limitations of present morphologic criteria for the diagnosis of left ventricular noncompaction.  One of the most interesting findings has been the confirmation of important overlaps between phenotypes of hypertrophic, dilated and restrictive cardiomyopathies with LVNC (1-4).

Is LVNC is an independent disease or a phenotypic variant of other primary cardiomyopathies?

Today it is not still clear when and whether LVNC is an independent disease or a phenotypic variant of other primary cardiomyopathies. Klassen et al. say: “One sarcomere gene mutation may trigger different pathological patterns of remodeling of the myocardium. Indeed, this discordance between the etiology of the disease and the “clinical syndrome” is one of the main findings of the present study”. This sentence could suggest that the phenotype associated with a particular genotype is unpredictable. We think that very frequently the lack of correlation is caused by our failure to adequately define and describe the phenotype. This has happened with the ACTC E101K mutation (the phenotype that was described as apical HCM is more consistent with noncompaction)(2,5) and probably with the  R243H MYH7 mutation (also apical HCM vs. noncompaction)(5) and the R131W TNNT2 mutation (dilated cardiomyopathy vs. noncompaction)(2,6).

The decision to call the disease noncompaction vs. hypertrophic or dilated cardiomyopathy is not always clear and different observers may give different names to the same condition. As Klassen et al. also say: “It is increasingly realized that the current nomenclature fails to adequately describe the substantial overlap between the classic cardiomyopathy syndromes. The shared molecular etiology of different cardiomyopathic phenotypes most likely reflects the interactions of genetic etiology, background modifier genes, and hemodynamic factors for the development of the phenotype”. We would add the interactions caused by the limitations of the diagnostic techniques and the interpretation biases of the clinicians.

Mutations in genes

More than 600 mutations in at least 8 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC, MYL2 and MYL3) have been described associated with hypertrophic, dilated and restrictive cardiomyopathies. This paper and other recent studies show that mutations in these genes may also be related with congenital abnormalities including not only left ventricular noncompaction, but also septal defects (2,7,8). Both septal defects and noncompaction are caused by alterations in the embryological development of the heart. It would be possible that abnormalities in the embryological heart development could also be implicated in the origin of sarcomeric hypertrophic or dilated cardiomyopathies, even though the clinical expression of this diseases is usually delayed until adolescence or appears even later in life. We strongly recommend the reading of the editorial from Dellefave and McNally that comments on this paper (9).


Clinical Implications

Screening for sarcomeric mutations appears as a good diagnostic strategy in patients with left ventricular noncompaction. The paper also remark how important is to recognise the presence of  overlapping phenotypes in cardiomyopathies. A precise phenotypic characterization and the recognition of these overlapping phenotypes in our families may give clues for the genetic diagnosis. It is also clear that there is a need for more clinical information about multiple genotyped families to establish accurate genotype-phenotype correlations. Finally, this paper is an example of the usefulness of genetic diagnosis to get a better understanding of the diseases, and to refine our clinical diagnostic criteria.


1. Klaasen S, Probst S, Oechslin E, et al. Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction. Circulation. 2008;117:2893-2901.

2. Monserrat L, Hermida-Prieto M, Fernandez X, et al. Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects. Eur Heart J. 2007;28:1953–1961.

3. Hoedemaekers YM, Caliskan K, Majoor-Krakauer D, et al. Cardiac beta-myosin heavy chain defects in two families with non-compaction cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated cardiomyopathies. Eur Heart J. 2007;28:2732-7

4. Biagini E, Ragni L, Ferlito M, et al. Different types of cardiomyopathy associated with isolated ventricular noncompaction. Am J Cardiol. 2006; 98:821-4.

5. Arad M, Penas-Lado M, Monserrat L, et al. Gene mutations in apical hypertrophic cardiomyopathy. Circulation 2005;112:2805–2811.

6. Mogensen J, Murphy RT, Shaw T, et al. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2004 ;44(10):2033-40.

7. Ching Y.H., Ghosh T.K., Cross S.J., et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nat. Genet. (2005) 37:423–428

8. Matsson H, Eason J, Bookwalter CS, et al. Alpha-cardiac actin mutations produce atrial septal defects. Hum Mol Genet. 2008;17:256-65.

9. Dellefave L, McNally EM. Sarcomere mutations in cardiomyopathy, noncompaction, and the developing heart. Circulation. 2008;117:2847-2849.

Notes to editor

By Dr. Lorenzo Monserrat. Cardiology Service. Complejo Hospitalario Universitario Juan Canalejo. A Coruña. Spain
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.