Genetic counselling for hypertrophic cardiomyopathy: are we ready for it?

Trials, Aug 2000

Hypertrophic cardiomyopathy (HCM) is a dominant genetic disorder of the myocardium associated with dysfunctional contractile proteins. The major risk of HCM is sudden cardiac death, which may occur even in asymptomatic carriers. Causes are highly heterogeneous. Over 140 different mutations in nine sarcomeric genes have been described to date. The majority of cases (80% or more) may eventually be traced to one of these genes. Although genetic counselling is suggested even if mutations are not known, molecular diagnosis implies new options such as carrier identification or - theoretically - preclinical risk stratification. A scheme according to which cardiologists and clinical and molecular geneticists could cooperate in counselling patients and managing HCM clinically is proposed.

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Genetic counselling for hypertrophic cardiomyopathy: are we ready for it?

0 Max-Planck-Institute for Physiological and Clinical Research , Bad Nauheim , Germany Hypertrophic cardiomyopathy (HCM) is a dominant genetic disorder of the myocardium associated with dysfunctional contractile proteins. The major risk of HCM is sudden cardiac death, which may occur even in asymptomatic carriers. Causes are highly heterogeneous. Over 140 different mutations in nine sarcomeric genes have been described to date. The majority of cases (80% or more) may eventually be traced to one of these genes. Although genetic counselling is suggested even if mutations are not known, molecular diagnosis implies new options such as carrier identification or - theoretically - preclinical risk stratification. A scheme according to which cardiologists and clinical and molecular geneticists could cooperate in counselling patients and managing HCM clinically is proposed. Introduction A young boy of 13 collapsed while running after the schoolbus. He could be resuscitated, but at the price of crippling brain damage. Clinical and genetic analysis subsequently revealed that he and his father were predisposed to hypertrophic cardiomyopathy (HCM): they were carriers of a missense mutation in the a -tropomyosin gene. The boy had no symptoms before he collapsed, whereas his father (in his early forties) had borderline myocardial hypertrophy in the interventricular septum associated with mild symptoms of cardiac disease. A daughter, age 11, also carried the mutation, but she was entirely asymptomatic. On average, penetrance of the disease gene was incomplete in this family. The boys collapse was presumably due to an episode of extreme ventricular tachycardia. Although the familial character of the disorder was suspected for some time prior to this event, genetic counselling had not been considered before the boy experienced cardiac arrest. In a second family the disease was associated with a high frequency of cardiac death. Three documented cases of premature sudden death in two generations, two of them in young adults, and numerous relatives being clinically affected imposed a heavy burden on the family. Early onset of the disease, syncopes, chest pain and progression to heart failure with no, or inconspicuous, hypertrophy were encountered. A few patients were only mildly affected. A mutation in the cardiac troponin T gene was identified by genetic analysis. All first-degree relatives of the patients were seeking counselling and asked for a DNA test. They were aware that this test offered a 50% chance of excluding the carrier status for those who were asymptomatic, in particular for children of parents at risk. Hence, parents also asked on behalf of their children. These are two different disease phenotypes randomly picked from numerous published or unpublished case reports of familial HCM. This is a heavily investigated disorder for which we have ample knowledge about causes and to a lesser degree about mechanisms. It is autosomal dominant and known to exist worldwide with a prevalence possibly as high as 1: 500 in the general population [1]. It may occur sporadically, but in the majority of cases it is a familial condition. Onset of symptoms is normally encountered during adolescence or in young adults, but first appearances may also be experienced in later decades of life. Symptoms are usually unspecific at first, and may include breathlessness, chest pain, syncopes and others. The diagnosis is confirmed by echocardiographic demonstration of myocardial hypertrophy, most frequently in the interventricular septum. Diagnostic criteria for the assessment of the disease in members of families at risk have been proposed [2]. Causes and mechanisms A major dysfunction in cardiac performance is impaired relaxation during diastole. Systolic functions are (at least in the beginning) not affected [3]. The most serious complication of HCM is ventricular fibrillation, which may cause sudden cardiac death. A typical problem is the extensive clinical variability of HCM, even within families where all patients have the same mutational background. The spectrum ranges from very mild or even asymptomatic to malignant courses. A multitude of causes has been identified. More than 100 different mutations (mostly missense mutations leading to amino acid exchanges in respective proteins) have been reported [4,5]. These mutations are in nine genes, all coding for contractile proteins cardiac motor proteins and their control components. HCM was, therefore, defined as a disease of the sarcomere [6]. The most frequently affected genes, accounting for more than 50% of all cases, coded for b -myosin heavy chain, cardiac troponin T and myosin binding protein-C. Mutational hot spots are rare and contribute only a few percent of the total genetic load of HCM. The mechanisms responsible for cardiac dysfunction and disease are not fully understood. Altered kinetics of crossbridge cycling of myosin and actin filaments are probably involved [7]. (...truncated)


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Hans-Peter Vosberg. Genetic counselling for hypertrophic cardiomyopathy: are we ready for it?, Trials, 2000, pp. 41-44, 1, DOI: 10.1186/cvm-1-1-041