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

Abstract

Background-Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of ␤-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of ␣-tropomyosin (TPM1). Routine genetic screening of HCM patients for specific mutations is anticipated to provide important diagnostic and prognostic information. The frequency and associated phenotype of these mutations in a large, unselected cohort of HCM is unknown. Methods and Results-A total of 293 unrelated HCM patients were genotyped for the presence of a benign mutation. DNA was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing. Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5 subjects with an ascribed benign mutation had already manifested clinically severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5 having a family history of sudden cardiac death, and 1 adolescent requiring an orthotopic heart transplant. Conclusions-These findings demonstrate the rarity of specific mutations in HCM and challenge the notion of mutation-specific clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and those patients with a benign mutation experienced a very serious clinical course. (Circulation. 2002;106:3085-3090.)

Prevalence and Spectrum of Thin Filament Mutations in an Outpatient Referral Population With Hypertrophic Cardiomyopathy

“…This is consistent with our previous studies, which demonstrated that the presence or absence of specific HCM mutations previously annotated as "malignant" or "benign" should not be used for prognosis or risk stratification. 27,28 From our previous studies, it also seems that the phenotype may not be a reliable predictor of the specific causative mutation. 27,28 In the subgroup of individuals harboring thin filament defects (nϭ18), no statistical difference was evident when compared with the rest of the cohort.…”

“…27,28 From our previous studies, it also seems that the phenotype may not be a reliable predictor of the specific causative mutation. 27,28 In the subgroup of individuals harboring thin filament defects (nϭ18), no statistical difference was evident when compared with the rest of the cohort. Our findings suggest that individuals with thin filament mutations had a similar degree of hypertrophy, age at presentation, and incidence of a family history of SCD as those without such mutations.…”

Recommendations for Physical Activity and Recreational Sports Participation for Young Patients With Genetic Cardiovascular Diseases

“…Mutation analysis for the purpose of risk stratification of sudden death, although prominently portrayed in the subspecialty literature, [1][2][3][4][7][8][9][10][11][12]16,[55][56][57][58][59][60][61][62][63][64][65][66][67] has limited practical impact on the present considerations. First, the diagnostic strategy of DNA analysis is time consuming, expensive, and limited to a small number of highly specialized research-oriented laboratories 1,2,8,64 -67 and thus is not yet routinely available to the practicing clinician for the purpose of patient management and formulation of exercise recommendations.…”

Hypertrophic Cardiomyopathy: Low Frequency of Mutations in the β-Myosin Heavy Chain (MYH7) and Cardiac Troponin T (TNNT2) Genes among Spanish Patients

“…Some of the TNNT2 mutations were associated with an adverse prognosis, and this raised the possibility that the identification of mutations in this gene may identify individuals at high risk of SCD, who would benefit from the implantation of a cardioverter defibrillator. Because some of the TNNT2 mutations have been associated with a high incidence of SCD in spite of minimal hypertrophy, the analysis of this gene could be of special interest in asymptomatic individuals with a family history of SCD (22,(24)(25)(26).…”