Mutations in Hotspot Region of MYH7 Gene Exon 23 Associated with Restrictive Cardiomyopathy

Abstract

Restrictive cardiomyopathy (RCM) is characterized by restrictive filling of the ventricles. The association between the variable expressivity and age at onset of disease and disease complexity with double and compound heterozygous state is associated with severity of disease phenotype in recent reports. Sharing of variants of sarcomere genes across cardiomyopathies has implication in clinical expression of different clinical phenotypes. The present study reports Sanger DNA sequencing of MYH7 gene, exon 23 from 30 unrelated RCM patients and 15 primary relatives from sporadic families with the hypothesis that RCM has common etiology with hypertrophic cardiomyopathy (HCM). Rare variant E949K and a de novo compound heterozygous mutation (p.E902K and p.D906N), in two RCM patients with early onset and no ventricular hypertrophy were found. These variants wereabsent in 50 dilated cardiomyopathy, 50 HCM patients and 15 primary relatives screened. The present report of rare and compound heterozygosity cases will further provide basis for the complexity and variable expressivity of phenotypes in patients in such complex diseases. The possible reasons for this phenotypic heterogeneity would be the presence of any other mutations in same chromosome or in different chromosome which is modifying the outcome of the causal mutation.

Clinical genetic testing in four highly suspected pediatric restrictive cardiomyopathy cases

“…RCM patients present with variable clinical manifestations. Patients with end-stage right heart failure are mainly characterized by systemic blood stasis (such as in the jugular vein), hepatomegaly, ascites, lower limb edema, and increased venous pressure [ 11 , 12 ], whereas some patients may have symptoms linked to left heart failure such as dyspnea, hemoptysis and wet rales at the bottom of the lung, low cardiac output, syncope, and even thromboembolism or sudden death [ 13 ]. Other non-specific manifestations of RCM include fatigue, shortness of breath, impaired activity tolerance, and slow physical development [ 11 – 13 ].…”

“…Mutations of a number of genes encoding for sarcomeric and cytoskeletal proteins are associated with the etiology of RCM with an incident rate of 33–66% (Table 2 ) [ 1 , 6 , 11 , 23 – 35 ]. TNNI3 was the first sarcomere gene reported to be pathogenic for RCM when mutated [ 11 ].…”

“…Mutations of a number of genes encoding for sarcomeric and cytoskeletal proteins are associated with the etiology of RCM with an incident rate of 33–66% (Table 2 ) [ 1 , 6 , 11 , 23 – 35 ]. TNNI3 was the first sarcomere gene reported to be pathogenic for RCM when mutated [ 11 ]. In contrast, CP is a disease of the pericardium resulting from chronic inflammation and/or scarring, and familiar CP is extremely rare.…”