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)