Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy.

Abstract

Three novel 63 cardiac myosin heavy chain (MHC) gene missense mutations, Phe513Cys, Gly716Arg, and Arg719Trp, which cause familial hypertrophic cardiomyopathy (FHC) are described. One mutation in exon 15 (Phe513Cys) does not alter the charge of the encoded amino acid, and affected family members have a near normal life expectancy. The Gly716Arg mutation (exon 19; charge change of +1) causes FHC in three family members, one of whom underwent transplantation for heart failure. The Arg719Trp mutation (exon 19; charge change of -1) was found in four unrelated FHC families with a high incidence of premature death and an average life expectancy in affected individuals of 38 yr. A comparable high frequency of disease-related deaths in four families with the Arg719Trp mutation suggests that this specific gene defect directly accounts for the observed malignant phenotype. Further, the significantly different life expectancies associated with the Arg719Trp vs. Phe513Cys mutation (P < 0.001) support the hypothesis that mutations which alter the charge of the encoded amino acid affect survival more significantly than those that produce a conservative amino acid change. (J. Clin. Invest. 1994. 93:280-285.)

Prevalence and Severity of “Benign” Mutations in the β-Myosin Heavy Chain, Cardiac Troponin T, and α-Tropomyosin Genes in Hypertrophic Cardiomyopathy

“…Initially, these 8 particular mutations appeared to confer a benign clinical phenotype (ie, near-normal life expectancy) based on a limited number of families: 1 large family with G256E, 12 1 family with F513C, 10 4 families with V606M, 13,14 1 family with R719Q, 15 and 1 family with L908V 19 in MYH7. The S179F-TNNT2 mutation has been reported in a single family, 16 and 3 families were evaluated for the D175N-TPM1 mutation.…”

“…10,13 Previously, we failed to identify a single patient with R719W. 28 In contrast to R719W, R719Q has been associated with nearnormal survival.…”

“…Within the ␤-myosin heavy chain gene (MYH7), at least 4 mutations have been ascribed as malignant mutations: R403Q, R453C, G716R, and R719W. 8,10,11 In contrast, 6 particular missense mutations in MYH7 (N232S, G256E, F513C, V606M, R719Q, and L908V), as well as the S179F mutation in troponin T (TNNT2) and the D175N mutation in ␣-tropomyosin (TPM1), have been designated as benign mutations with no increased risk of SCD. 8 -10,12-17 Several studies have reported exceptions to these genotypephenotype correlations [12][13][14]18,19 ; however, the veracity with which the genetic substrate predicts the clinical outcome and the frequency of specific mutations are unknown.…”

Hypertrophic cardiomyopathy: from gene defect to clinical disease

“…More than 80 unique mutations have been reported that alter one amino acid residue in the globular head or head-rod junction of the b-myosin heavy chain. These mutations are expressed with a high degree of penetrance and most affected individuals ( ~ 90%) exhibit significant myocardial hypertrophy on two-dimensional echocardiography studies by age 20 years [16] (Fig 2A). Despite nearly complete disease penetrance and significant hypertrophy, survival in HCM caused by a β-cardiac myosin heavy chain mutation varies considerably and is, in part, mutation-specific.…”

Disrobing the Emperor (Heart) Without Destroying the Dignity of Super-Normality

“…Genotype/phenotype correlation studies have been insightful, leading to the observation that FHCM seldom develops before puberty. [1][2][3][4] There are also certain age-dependent trends observed for specific genes. Myosin heavy chain mutations tend to be associated with a high incidence of sudden death, onset in the second and third decades of life, 90% to 100% penetrance, and significant hypertrophy.…”