Familial restrictive cardiomyopathy – TNNI3, ACTC1, MYH7 and TNNT2 genes.


Family restrictive cardiomyopathy or restrictive cardiomyopathy (RCM) is a genetic form of heart disease in which the heart muscle is stiff and cannot completely relax after each contraction. An altered muscle relaxation causes blood to be retained in the atria and lungs, which reduces the amount of blood in the ventricles.

The first signs and symptoms in children are lack of weight gain and growth retardation, fatigue and fainting. Children who are severely affected may also have abnormal swelling or edema, increased blood pressure, hepatomegaly, ascites and pulmonary congestion. Some children with family restrictive cardiomyopathy do not show obvious signs or symptoms, but they may die suddenly due to heart failure. Without treatment, most affected children survive only a few years after being diagnosed. Often affected adults first develop shortness of breath, fatigue and a decreased ability to exercise. In addition, some people have arrhythmia, palpitations, dizziness and abnormal blood clots. Without treatment, approximately one third of affected adults do not survive more than five years after diagnosis.

This process is due to mutations in several genes; however, mutations in the TNNI3 gene (troponin I3, cardiac type), located on the long arm of chromosome 19 (19q13.42) are one of the main causes of this disease. This gene encodes troponin I, which is found exclusively in the heart. This protein is one of three proteins that make up the troponin protein complex in cardiac muscle cells. The troponin complex is associated with sarcometers. This complex, along with calcium, helps regulate the contraction of the heart muscle. For the heart to beat normally, the heart muscle must contract and relax in a coordinated manner. Troponin I helps coordinate cardiac contraction. When calcium concentrations are low, the troponin complex binds to the thin filament. This blocks the union of the interaction between the thick and thin filaments that are needed for muscle contraction. An increase in calcium concentrations causes structural changes in another protein called the troponin C complex, which subsequently activates the troponin complex to shed the thin filament, allowing the heart muscle to contract.

Approximately 10 mutations in the TNNI3 gene have been identified that lead to the development of family restrictive cardiomyopathy. Most of these mutations consist of amino acid changes in the troponin I protein, which alters the protein´s function. As a consequence, the altered protein cannot bind to actin and the relaxation of the heart muscle is interrupted, resulting in abnormal heart function, poor blood flow and other signs and symptoms, such as fatigue and fainting.

Mutations in the ACTC1 (actin alpha cardiac muscle 1), MYH7 (myosin heavy chain 7) and TNNT2 (troponin T2, cardiac type) genes have been identified that may lead to the development of family restrictive cardiomyopathies. The mutations identified in these genes represent a small percentage of cases. In some people with family restrictive cardiomyopathy, a mutation identified in none of the known associated genes has not been identified and the cause of the disorder process in these individuals is unknown.

This disease is inherited with an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient for the alteration to be expressed. In some cases, an affected person inherits the mutation of an affected parent. Other cases are due to new mutations in the gene and occur in people with no history of the disease in their family.

Tests performed in IVAMI: in IVAMI we detect mutations associated with family restrictive cardiomyopathy, by means of complete PCR amplification of the exons of the TNNI3, ACTC1, MYH7 and TNNT2 genes, respectively, and their subsequent sequencing.

Recommended samples: blood taken with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).