Familial hypertrophic cardiomyopathy (FHCM) is a genetic disorder affecting the heart muscle, leading to the thickening (hypertrophy) of the left ventricle, the main pumping chamber. This condition is inherited in an autosomal dominant manner, meaning that an affected individual has a 50% chance of passing the genetic mutation to each of their children. It is a relatively common cardiovascular disease that affects approximately one in 500 people. It is caused by pathogenic variants in more than 11 genes that code for proteins constituting the contractile structure or sarcomere of cardiac muscle cells.
Familial hypertrophic cardiomyopathy genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of familial hypertrophic cardiomyopathy include:
- Hypertrophy: The primary characteristic of FHCM is the abnormal thickening of the heart muscle, particularly the walls of the left ventricle. This hypertrophy can affect the heart's ability to pump blood effectively.
- Genetic Inheritance: FHCM is caused by gene mutations that provide instructions for proteins involved in the structure and function of the heart muscle. The most commonly affected genes are MYH7 and MYBPC3, but mutations in other genes can also be responsible.
- Autosomal Dominant Inheritance: Individuals with FHCM have a 50% chance of passing the genetic mutation to each of their offspring. The severity and onset of symptoms can vary among affected family members.
- Arrhythmias: FHCM can lead to abnormal heart rhythms (arrhythmias), which can increase the risk of fainting, palpitations, and in severe cases, sudden cardiac arrest.
- Heart Failure: In some cases, the thickening of the heart muscle can lead to heart failure, a condition where the heart cannot pump blood effectively.
Diagnosis of FHCM typically involves a combination of clinical evaluation, family history assessment, imaging studies (such as echocardiography), and genetic testing. Genetic testing can identify the specific genetic mutations associated with the condition and help confirm the diagnosis.
Management of familial hypertrophic cardiomyopathy may involve medications to alleviate symptoms, control arrhythmias, and manage heart failure. In some cases, surgical interventions or implantation of a defibrillator may be recommended.
Regular monitoring and follow-up care are essential for individuals with FHCM, mainly due to the risk of sudden cardiac events. Family members of affected individuals may also benefit from genetic testing and regular cardiovascular assessments.
Given the genetic nature of FHCM, genetic counseling is crucial for affected individuals and their families. It can provide information about the inheritance pattern, help assess the risk of passing the condition to future generations, and guide family planning decisions. Early diagnosis and appropriate management can improve outcomes and quality of life for individuals with familial hypertrophic cardiomyopathy.
Although the etiopathogenesis of the disease is not fully elucidated, 40-60% of HCM cases are estimated to have a genetic origin. Numerous genes coding for sarcomere proteins that may play a role in this disease have been identified. The two most frequently mutated genes, MYBPC3 and MYH7, account for approximately 50% of all cases of familial hypertrophic cardiomyopathy. These genes encode for a myosin-binding protein and the beta isoform of the myosin heavy chain, respectively.
The variants c.746G>A (p.Arg249Gln) and c.1207C>T (p.Arg403Trp) are located in the MYH7 gene encoding for the beta subunit of the myosin heavy chain. Both mutations impact the secondary structure of the protein, causing a decrease in its activity. They are two of the most frequent mutations in HCM patients.
The variant c.173G>A (p.Arg58Gln) located in the MYL2 gene induces an amino acid change with an impact on the secondary structure of the protein, hindering its ability to bind calcium ions, thereby affecting the regulation of cardiac contraction. This variant has been observed in patients with symptoms and asymptomatic individuals. Within the same gene, the c.52T>C variant (p.Phe18Leu), located at the N-terminal end, causes a marked reduction in the rate of shortening of the cardiac discharge.
The c.539A>G (p.Glu180Gly) variant, located in the TPM1 gene encoding tropomyosin 1, has been reported in several studies to be pathogenic in association with HCM. Functional studies indicate that c.539A>G affects actin-myosin interaction, impairing the contractile capacity of muscle fibers. Affecting the same gene, the c.523G>A mutation (p.Asp175Asn) is located in the calcium-binding domain, decreasing the enzyme's activity. It is especially prevalent in the Finnish population, in 11% of HCM cases.
The TTN gene codes for titin, a large sarcomere protein involved in muscle contraction. It has been observed that the c.2219G>T variant can cause HCM.
Alterations in the PRKAG2 gene, which codes for the gamma-2 subunit of the AMPK enzyme, have been linked to abnormalities in glucose storage in the heart. The c.1199C>A or p.Thr400Asn variant of the PRKAG2 gene is associated with early activation of the NF-kB and Akt signaling pathways that produce cardiac hypertrophy.
There is no association between the affected gene and the symptoms and prognosis of HCM. However, studies suggest that several mutations in compound heterozygosis affecting the same or different sarcomeric genes may produce more severe phenotypes.
The genetic test of familial hypertrophic cardiomyopathy analyzes the 90 most frequent pathogenic mutations of the MYH7 gene plus the 3 most frequent pathogenic mutations of the MYL2 gene plus the 5 most frequent pathogenic mutations of the PRKAG2 gene plus the 6 most frequent pathogenic mutations of the TPM1 gene plus the 2 most frequent pathogenic mutations of TTN gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
