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

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.

Comments

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. 

Conclusion:

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.