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Sarcomere Gene Mutations in Isolated Left Ventricular Noncompaction Cardiomyopathy Do Not Predict Clinical Phenotype

Left ventricular noncompaction of the myocardium (LVNC) is considered an unclassified cardiomyopathy in the European Society of Cardiology (ESC) classification scheme for heart muscle disease. It is characterised by prominent trabeculations and deep intertrabecular recesses in association with a thin, compacted epicardial muscle layer. In some patients, LVNC is associated with left ventricular dilatation and systolic dysfunction.

LVNC occurs in association with many congenital cardiac disorders, but it is still not clear whether isolated LVNC is a separate cardiomyopathy or a morphological trait shared by phenotypically distinct cardiomyopathies. The prevalence of LVNC, estimated from retrospective studies, ranges from 4.5 to 26 per 10,000 adult patients referred for echocardiography. Many patients are completely asymptomatic but some present with congestive heart failure, thromboembolism and arrhythmias, including sudden cardiac death.

Familial disease is estimated to occur in 18% to 50% of adults with isolated LVNC, mostly with an autosomal dominant mode of inheritance. Numerous mutations in genes encoding sarcomere proteins have been reported. In 2008, using a panel of 6 sarcomere protein genes - MYH7, ACTC1, TNNT2, TNNI3, MYL2 and MYL3 – the authors of this paper of the month reported that LVNC was associated with mutations in sarcomere genes (ß-myosin heavy chain (MYH7) cardiac troponin T (TNNT2) and alpha-cardiac actin (ACTC1)) in 17% of 63 adult patients with LVNC. Last year, in a study by Hoedemakers et al, mutations in 11 genes were reported in patients with LVNC: 6 sarcomere protein; 2 calcium-handling genes; and other cardiomyopathy genes such as lamin A/C (LMNA), ZASP (LDB3), and Taffazin (TAZ). These variants were present in 41% (23 of 56) of the tested probands. This month’s paper extends these findings to an analysis of disease penetrance and genotype-phenotype correlations in families.

Myocardial Disease

Summary of the paper

In this paper, the authors describe the prevalence of 8 sarcomere protein disease genes in 63 adult patients with isolated LVNC. The main purpose of the study was to conduct a combined genetic and phenotypic analysis to compare mutation-positive versus mutation-negative probands.

A cohort of unrelated Caucasian individuals of Western European descent (43 men and 20 women; mean age at diagnosis, 40.2 +/- 15.6 years; range 15 to 70 years) underwent genetic screening. Using genomic DNA samples, denaturing high performance liquid chromatography analysis was performed and samples with an abnormal peak were sequenced. Probands and available family members were evaluated by history taking, review of medical records, physical examination, 12-lead electrocardiography, 24 hour electrocardiographic monitoring, and transthoracic echocardiography.

Eighteen mutations were identified in 29% of probands. Fifteen distinct heterozygous mutations were found in 5 sarcomere protein genes: MYH7, MYBPC3, TPM1, ACTC1, and TNNT2. No mutations were found in TNNI3, MYL2 and MYL3. Mutations occurred most frequently in MYH7 and MYBPC3 (13% and 8%, respectively). The frequencies of mutations in remaining genes were: 3% in TPM1, 3% in ACTC1 and 2% in TNNT2. Eight of the 15 distinct heterozygous mutations were novel: 6 in MYH7, 1 in TPM1 and 1 in MYBPC. The majority of mutations were missense mutations (13/18), but 3 splice-site mutations, and 2 deletions, 1 with and 1 without a frame-shift were identified. No probands carried multiple sarcomere mutations. Seven of the 15 distinct mutations have been described before in patients with dilated and hypertrophic cardiomyopathies.

Familial disease was present in 16 probands (25%) of which 8 patients were mutation-positive and 8 were mutation-negative for sarcomere genes. Echocardiography revealed LVNC in affected family members, except for one family in which DCM was present in one neonate.

Phenotypic comparison between the 18 mutation-positive and 45 mutation-negative patients was performed. The number of symptomatic versus asymptomatic patients, and the number of tachyarrhythmias were similar in the two groups at the time of diagnosis. Echocardiographic criteria were also indistinguishable. There was no difference between the two groups with regard to the number of implantations of a cardiac defibrillator. Patients that received a cardiac transplant or died were more likely to be found in the mutation-negative group (p<0.048). However, the Kaplan-Meier survival curve for the combined end-point heart transplantation or death did not demonstrate any difference between the two groups.


Despite the negative findings concerning the phenotypic comparison between mutation-positive and mutation-negative probands, we believe that this paper is a very important contribution to establish the relevance of genetic testing and screening in LVNC.

It confirms sarcomere gene mutations as an important cause of LVNC, present in nearly one third of the probands. Mutations in the genes encoding the thick and thin filaments of the cardiac sarcomere typically cause hypertrophic and dilated cardiomyopathy, but there is some evidence that different phenotypes related to MYH7 mutations are caused by mutations clustering in different areas of the gene. Further work examining the role of MYH7 and other sarcomere proteins in cardiac development are clearly necessary.

Clinical and echocardiographic screening is already indicated to detect asymptomatic family members with LVNC, because of the potentially increased risk for arrhythmias, myocardial dysfunction and/or thromboembolic events. In addition, evidence is growing that genetic evaluation can also be highly useful for identifying at-risk relatives without the morphological changes.

Long-term prospective studies with a larger cohort are needed to detect possible relationships between the type of mutation, genetic modifiers and clinical phenotype. Targeted next-generation sequencing (NGS) platforms and whole-exome strategies are able to interrogate many genes simultaneously. This approach could identify novel non-sarcomeric gene mutations and modifier genes. Modifier genes could explain the variable expressivity (e.g. some of the mutations were described in HCM or DCM). NGS platforms can also address structural variation and intronic variants, both poorly studied in cardiomyopathies. Early phenotyping of mutation carrier relatives could also contribute to the refinement of genotype-phenotype correlations. 


Improved knowledge of the genetic determinants of LVNC holds the promise of contributing towards a better understanding of disease mechanisms, very likely related to the myocardium development process. This is probably true for LVNC, as well as for other (phenotypically) distinct cardiomyopathies.


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Notes to editor

Presented by: Luis Lopes(1,2) and Perry Elliott (2)

1 - Gulbenkian Doctoral Programme for Advanced Medical Education, Portugal
2 - The Heart Hospital, University College London, U.K.
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.