Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations.

Abstract

BACKGROUND We have previously described two distinct mutations in the beta-myosin heavy chain gene with markedly different clinical presentations and outcome: The 908Leu-->Val mutation was associated with a low disease penetrance and a benign prognosis. In contrast, the 403Arg-->Gln mutation in a Caucasian kindred was associated with a 100% disease penetrance and high incidence of sudden cardiac death. Recently, another mutation, 606Val-->Met, has been reported to be associated with "near normal survival" and offered as evidence for the benign nature of neutral charge substitutions. METHODS AND RESULTS We report (1) a large kindred (245 family members at risk of inheriting the disease gene) with a 256Gly-->Glu mutation characterized by a similar disease penetrance in adults and in children (56% and 60%, respectively) and a cumulative sudden cardiac death rate of only 2% at 50 years of age, (2) a kindred with the 606Val-->Met mutation with four sudden cardiac deaths in eight affected individuals, and (3) a Korean kindred with the 403Arg-->Gln mutation. Although the disease occurred early and was associated with a high prevalence of myocardial ischemia in both of our kindreds with the 403Arg-->Gln mutation, no sudden cardiac death or syncope has occurred in the Korean kindred. Furthermore, in the Caucasian kindred, all patients had nonobstructive hypertrophic cardiomyopathy, but most of the patients in the Korean kindred had left ventricular outflow obstruction. CONCLUSIONS The conclusions are as follows: (1) Although several sudden cardiac deaths are sufficient to establish that a mutation is malignant, study of a large kindred is necessary to be certain that a mutation is benign. To date, only the 908Leu-->Val and the 256Gly-->Glu mutations satisfy this requirement. (2) The 256Gly-->Glu mutation demonstrates that not all mutations that result in a charge change are malignant. (3) Conversely, the 606Val-->Met mutation is malignant in some kindreds; hence, despite the absence of a charge change, minor substitutions in critical regions of beta-myosin heavy chain protein may also have serious consequences. (4) The diverse ethnic origins of the two 403Arg-->Gln kindreds provide evidence suggesting that the identical mutation occurred independently and was associated with different genetic backgrounds. Their distinct phenotypes underline the importance of modifying genes and nongenetic factors.

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

“…In spite of exceptions to previously published genotype-phenotype correlations, [12][13][14]18,19 hopes that genetic testing will become a routine clinical test with prognostic value remain. 9,23-26 An HCM gene chip containing known mutations has been reported.…”

“…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. From a cohort of nearly 300 unrelated individuals with HCM seen at a single tertiary referral center, we sought to determine the frequency of 8 published benign mutations and to examine the clinical course of the individuals harboring these mutations.…”

Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

“…To date more than 70 different mutations have been identified in the MYH7 gene (Table 1). Some are associated with sudden death (p.R403Q), but several also have a benign phenotype (p.V606M) (Epstein et al 1992;Fananapazir and Epstein 1994).…”

Hypertrophic Cardiomyopathy Caused by a Novel α-Tropomyosin Mutation (V95A) Is Associated With Mild Cardiac Phenotype, Abnormal Calcium Binding to Troponin, Abnormal Myosin Cycling, and Poor Prognosis

“…Clinical characteristics of HCM vary from a benign asymptomatic course to severe heart failure and sudden death. Molecular genetic studies [1][2][3][4][5][6][7] have shown that HCM may be caused by mutations in several sarcomeric genes, including TPM1, that may determine clinical outcome. Most ␤-myosin heavy chain gene (MYH7) mutations, such as R403Q, are associated with high disease penetrance and a poor prognosis.…”

“…4 In contrast, the few MYH7 mutations that have a benign prognosis, such as L908V and G256E, are associated with a low disease penetrance. 5 HCM caused by myosin-binding protein-C gene (MYBPC3) is characterized by low disease penetrance (Ϸ60%), mild cardiac phenotype in young subjects, and a favorable prognosis. [1][2][3] HCM due to cardiac troponin-T gene (TNNT2) is usually associated with relatively low disease penetrance (Ϸ80%) and mild LVH but a high incidence of sudden death.…”