A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1S (CMD1S) is caused by heterozygous mutation in the MYH7 gene (160760) on chromosome 14q12.

Mutation in the MYH7 gene has also been associated with left ventricular noncompaction (LVNC5), hypertrophic cardiomyopathy (CMH1; 192600), and myosin storage myopathy (608358).

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200); for a similar discussion of left ventricular noncompaction, see LVNC1 (604169).

Kamisago et al. (2000) studied affected members of a large 4-generation family segregating autosomal dominant dilated cardiomyopathy (CMD). Seventeen family members had dilated cardiomyopathy without conduction system disease, skeletal muscle dysfunction, or other phenotypes. The authors noted that previous clinical studies of 12 affected individuals showed no evidence of ventricular hypertrophy. In many family members, the onset of disease occurred early in life: one patient was hospitalized with heart failure at 2 years of age; another developed heart failure followed by sudden death at 20 years of age; and another underwent cardiac transplantation for end-stage heart failure at 23 years of age. Histopathologic study of the explanted heart from the last patient showed mildly increased interstitial fibrosis without myocyte or myofibrillar disarray.

Left Ventricular Noncompaction 5

Sasse-Klaassen et al. (2003) studied a family (designated 'INVM-101') segregating autosomal dominant left ventricular noncompaction (LVNC), in which there were 5 affected individuals over 2 generations. The proband underwent diagnostic evaluation because of inverted T waves seen on routine electrocardiogram at 60 years of age, and was found to have marked noncompaction confined to the left ventricular apex and an enlarged left ventricle with a left ventricle end-diastolic diameter (LVEDD) of 66 mm and reduced systolic function (left ventricle fractional shortening, 14%; left ventricle ejection fraction, 27%). Two asymptomatic daughters with LVNC were identified at 40 and 23 years of age, respectively. Sasse-Klaassen et al. (2003) also studied 2 brothers with LVNC ('family INVM-107'). The probands from both families were originally characterized by Oechslin et al. (2000).

Klaassen et al. (2008) provided follow-up on families INVM-101 and INVM-107, stating that clinical evaluation of family 101 was remarkable for the very pronounced morphology of LVNC. The proband, who had suffered a stroke and systemic peripheral emboli, had an affected brother who initially presented with decompensated heart failure and pulmonary emboli; both patients remained stable over a period of 8 years. Other affected members of family INVM-101 fulfilled morphologic LVNC criteria but were clinically asymptomatic. The 4 affected individuals in family INVM-107 all had noncompaction involving the apex and mid-left ventricular wall, and the right ventricle was involved as well in 2 patients. The 25-year-old male proband, who had been diagnosed with LVNC after developing cardiogenic shock and pulmonary and systemic peripheral emboli, received a cardiac transplant at age 26 years. His 32-year-old affected brother also carried the mutation, as did their 65-year-old mother, who had typical LVNC morphology but remained clinically asymptomatic. The brother's son fulfilled criteria for LVNC at 2 years of age.

Uro-Coste et al. (2009) studied a family in which the mother had myosin storage myopathy (608358) and later developed hypertrophic cardiomyopathy (CMH1; 192600), whereas the daughter had early symptomatic LVNC. The mother presented at age 30 years with proximal muscle weakness, which progressed to the point of her being wheelchair-bound by age 48 years. At age 51, hypertrophic cardiomyopathy was diagnosed; echocardiography revealed no atrial or ventricular dilatation, and no abnormal appearance of the ventricular walls. Skeletal muscle biopsy at age 53 years showed subsarcolemmal accumulation of hyaline material in type 1 fibers. Her 24-year-old daughter presented with heart failure at 3 months of age and was diagnosed with early-onset cardiomyopathy. Angiography revealed a less-contractile, irregular 'spongiotic' wall in the inferior left ventricle; on echocardiography, the left ventricle was dilated and fulfilled the criteria for LVNC, with a severely thickened, 2-layered myocardium and numerous prominent trabeculations and deep intertrabecular recesses. The daughter did not complain of muscle weakness, but clinical examination revealed bilateral wasting of the distal leg anterior compartment and she had some difficulty with heel-walking.

LVNC With Oligogenic Inheritance

Gifford et al. (2019) identified a 2-month-old infant with congestive heart failure requiring mechanical ventilation and inotropic support in whom echocardiography revealed severely depressed left ventricular function and deep left ventricular trabeculations, characteristic of left ventricular noncompaction (LVNC). The family history disclosed a sib who suffered fetal demise at 24 weeks' gestation. Examination of histologic sections revealed that the fetus suffered from biventricular noncompaction, based on the deep recesses in the myocardial walls of both ventricles, right ventricular dilation, and widespread fibrosis. Cardiac imaging of living immediate family members exposed previously undetected evidence of LVNC in a 4-year-old sib and subtle signs of LVNC in the father. The proband's paternal grandfather had a history of arrhythmia but, similar to the extended family, no cardiac functional or structural abnormalities were detected. These findings suggested vertical transmission of LVNC from the father with a markedly increased severity of disease and age of onset in offspring.

In a large 4-generation family segregating autosomal dominant dilated cardiomyopathy (CMD), Kamisago et al. (2000) performed genomewide linkage analysis and obtained a maximum lod score of 5.11 on chromosome 14q11.2-q13 at D14S990. Haplotype analysis defined a 14-cM critical interval between D14S283 and D14S597.

In a large 4-generation family segregating autosomal dominant dilated cardiomyopathy mapping to chromosome 14q11.2-q13, Kamisago et al. (2000) analyzed the candidate gene MYH7 (160760) and identified heterozygosity for a missense mutation (S532P; 160760.0022). In an unrelated family with CMD, in which a father and 2 daughters were affected, the authors identified a different heterozygous missense mutation (F764L; 160760.0023).

In a series of 46 young patients with CMD, Daehmlow et al. (2002) screened 4 sarcomere genes and identified 2 probands with heterozygous missense mutations in the MYH7 gene: A223T (160760.0026) and S642L (160760.0027). The patients were diagnosed at ages 35 years and 18 years, respectively.

Klaassen et al. (2008) analyzed 6 genes encoding sarcomere proteins in 63 unrelated adult probands with left ventricular noncompaction but no other congenital heart anomalies. They identified 7 different heterozygous mutations in the MYH7 gene in the probands from 4 families, 2 of which were previously studied by Sasse-Klaassen et al. (2003) (families INVM-101 and INVM-107), and in 4 sporadic patients, respectively (see, e.g., 160760.0040-160760.0042). Klaassen et al. (2008) stated that the most frequent symptom at presentation for patients with MYH7 mutations was dyspnea, followed by atypical chest pain and palpitations. LVNC was always present in the ventricular apex, and in all but 2 probands, the midventricular inferior and lateral walls were involved, whereas there was sparing of the basal left ventricular segments. Five of 8 probands had biventricular involvement. Left ventricular end-diastolic dimensions were enlarged and systolic function was impaired in 5 of 8 probands, and heart failure was present at initial diagnosis or occurred during follow-up in all but 2 probands. Stroke or pulmonary or systemic peripheral thromboemboli occurred in 4 of 8 probands.

In a mother with myosin storage myopathy (608358) and hypertrophic cardiomyopathy (CMH1; 192600) and her daughter with early symptomatic LVNC, Uro-Coste et al. (2009) identified heterozygosity for an L1793P mutation in the MYH7 gene (160760.0037).

In an analysis of the MYH7 gene in 141 white probands of western European descent diagnosed with Ebstein anomaly (see 224700), Postma et al. (2011) identified heterozygous mutations in 8 (see, e.g., 160760.0045 and 160760.0046). Of these 8 probands, LVNC was present in 7 and uncertain in 1, whereas none of the 133 mutation-negative probands had LVNC. Evaluation of all available family members of mutation-positive probands revealed 3 families in which additional mutation-positive individuals had cardiomyopathy or congenital heart malformations, including type II atrial septal defect, ventricular septal defect, bicuspid aortic valve, aortic coarctation, and pulmonary artery stenosis/hypoplasia.

Oligogenic Inheritance of LVNC

Gifford et al. (2019) studied a family in which LVNC segregated with mutations in 3 genes. Using whole-exome sequencing, Gifford et al. (2019) identified 2 previously undescribed heterozygous mutations in a proband with LVNC, 2 affected sibs, and their mildly affected father: a leu387-to-phe (L387F) mutation in the MYH7 gene, and a gln670-to-his (Q670H) mutation in the MKL2 gene (609463), encoding a myocardin-related transcription factor. The L387F mutation occurs at a highly conserved residue in the ATPase domain of the MYH7 protein, and mutations in MYH7 have been implicated in LVNC, hypertrophic cardiomyopathy, and dilated cardiomyopathy. The Q670H mutation occurs at a highly conserved residue near the leucine zipper domain of MKL2; Gifford et al. (2019) found that the Q670H mutant protein had reduced transcriptional activity in vitro compared to wildtype MKL2. The Q670H MKL2 mutation was also found in the proband's unaffected uncle and grandfather, indicating that this variant is not sufficient to cause cardiac dysfunction. The L387F MYH7 mutation was shown to have arisen de novo in the father. Given the marked increase in severity of disease in the 3 children compared to their father, Gifford et al. (2019) investigated whether variants inherited from the unaffected mother might serve as genetic modifiers of the LVNC phenotype. Using whole-exome sequencing followed by filtering for cardiac enrichment, the authors identified a ala119-to-ser (A119S) substitution in the NKX2-5 gene (600584) in the sibs and their mother. This variant was found at a minor allele frequency (MAF) of 0.0012 in the ExAC database.

Using CRIPSR-Cas9, Gifford et al. (2019) created mice with orthologous variants in each of the genes mutant in affected individuals with LVNC in the family studied by them. Heterozygous MYH7-L387F animals were observed at the expected mendelian ratio, but homozygous animals died at embryonic day 9.5 with evidence of heart failure. Mendelian ratios were observed for the NKX2-5 A118S and MLK2 Q664H mice, and although animals homozygous for each did not exhibit evidence for cardiac dysfunction by echocardiography, they had subtle abnormalities in the ventricular wall before the first week of life. Gifford et al. (2019) next investigated whether heterozygosity for all 3 of the variants produced an LVNC-like phenotype in mice. Immunohistochemistry at postnatal day 3 revealed mild hypertrabeculation and apical recesses in single or double heterozygous mice; however, triple heterozygous mice exhibited deep trabeculations in the left ventricular wall that were similar to those seen in patients and in the autopsy of the affected child in the family described.

Gifford et al. (2019) generated patient-specific induced pluripotent stem cells (iPSCs) from multiple family members and differentiated them to cardiomyocytes using WNT pathway modulation. RNA sequencing on day 8 of cardiomyocyte differentiation revealed downregulation of gene sets associated with cell adhesion and extracellular matrix deposition in the symptomatic case. Gene ontology analysis revealed upregulation of cell cycle and cardiac developmental genes in cells derived from the symptomatic LVNC case, which was similar to that observed in triple-heterozygous mice. A statistically significant overlap was observed between differentially expressed genes shared by the asymptomatic and symptomatic individuals' cell lines compared with those from unaffected individuals. However, the fold change of many key genes was often greater in the cell line derived from the individual diagnosed with symptomatic LVNC and harboring all 3 genetic variants. To infer gene dysregulation that may have been related to disruption of NKX2-5 function due to the A119S SNV, Gifford et al. (2019) used published NKX2-5 ChIP-sequencing data and found that genes expressed at higher levels in the triple heterozygous childhood-onset individual compared with her father were significantly closer to NKX2-5 binding events compared with gene sets identified in alternative differential expression scenarios and randomly permuted data. Gifford et al. (2019) concluded that analysis of murine hearts and human iPSC-derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant's contribution as a genetic modifier.