Abstract 841: Mutations in MYH7 Are Also Associated with Idiopathic Familial Restrictive Cardiomyopathy
Background: Mutations in MYH7-encoded cardiac beta myosin heavy chain have been associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and most recently with HCM with restrictive physiology and an infantile restrictive cardiomyopathy phenotype. We sought to determine the prevalence and spectrum of MYH7 mutations in an idiopathic RCM cohort.
Methods: 10 unrelated patients (Mean left atrial diameter 50.6 ± 5.9 mm, LVEDD 37.8 ± 15.3 mm, LVEF, (%) 57 ±4.24 and Abnormal ECG (%) 80) were analyzed for mutations in the 8–24 translated exons of MYH7 by polymerase chain reaction, denaturing high performance liquid chromatography and direct DNA sequencing.
Results: A novel MYH7 missense mutation (p.Arg721Lys) in exon 19 was detected in 1 RCM patient(10%). The mutation, p.Arg721Lys was discovered in a symptomatic female diagnosed at 46 years. She had one episode of syncope and frequent episodes of sudden onset of palpitations associated with sweating. Echocardiography revealed cardiomegaly with biatrial enlargement and normal ventricular function. The ventricular wall thickness was found to be normal (max 12 mm). Cardiac catheterization showed features consistent with restrictive physiology. She died at the age of 47 due to progressive congestive cardiac failure. Endomyocardial biopsy showed myofibre disarray and hypertrophy indicative of HCM like features histologically. Her 23 year old son, who had features consistent with early restrictive physiology, was also found to be carrier of the p.Arg721Lys mutation; this mutation was absent in proband’s unaffected son suggesting familial association of this mutation with RCM. p.Arg721Lys involves a residue that is conserved across species and localizes to converter domain of the MYH7 protein; any structural aberration in this region could result in the anomalous ATPase function of MYH7. p.Arg721Lys mutation was absent in 100 healthy controls.
Conclusion: Mutations in MYH7 provide a putative pathogenic mechanism for RCM in approx. 10% of cases. Moreover, p.Arg721Lys provides another example of phenotypic plasticity whereby MYH7 mutations appear to confer susceptibility for distinct and seemingly divergent cardiomyopathy phenotypes, RCM, DCM and HCM.