Introduction 

Cardiomyopathy (CM) is a rare, heterogeneous disorder characterised by structural, mechanical and electrical abnormalities of the myocardium. Although it can be inherited, paediatric CM can also arise from infections, tachyarrhythmias, and abnormalities in the coronary arteries, the vessels supplying the heart muscles with blood. Genetic testing is becoming “the golden standard of care” as a key contributing factor in the process of diagnosing, case surveilling and management in CM. However, there is increasing research surrounding gene-specific therapies for providing better diagnostic insights.¹

CM is one of the leading causes of heart failure amongst the younger population globally.² Genetic testing enables clinicians to classify and identify individuals with no symptoms, who may be at risk of developing cardiomyopathy. It also helps identify early signs of CM in children, which is essential for effective treatment and management of disease progression.³ 

This article presents the main genes contributing to CM in children and how genetic testing can be used for better disease prognosis in paediatric CM.

Overview of paediatric cardiomyopathy

There is currently a lack of data surrounding the diagnostic yield of genetic testing for children affected with cardiomyopathy.⁴

There are several types of pediatric CM, these include:

• Dilated cardiomyopathy (DCM) - enlargement of the left ventricle (LV), thinner ventricular wall and decreased systolic function, hence the heart becomes too weak to pump blood throughout the body²
• Hypertrophic cardiomyopathy (HCM) - characterised by increased thickness of the left ventricular wall, and diastolic dysfunction, making the heart too stiff to effectively pump blood^2,5
• Restrictive cardiomyopathy (RCM) - increased stiffness of the myocardium, resulting in difficulty with both systolic and diastolic function (during both the active pumping and relaxation phases of the heart’s contraction), which means the ventricles cannot adequately fill with blood, often resulting in heart failure²
• Arrhythmogenic cardiomyopathy (ACM) - a rare form of CM, characterised by the build-up of fatty tissue in the ventricular wall, replacing myocardium⁶

Although the different types of CM can be distinguished by their unique structural changes, children can experience a mixed category of symptoms where HCM can progress into DCM.¹

Common symptoms of CM in younger children are dyspnea (shortness of breath), tachypnea (shallow, quick breaths), and poor feeding, whereas older children often experience exercise intolerance, easy fatigability, angina (chest pain) and palpitations.^1,2 It is essential to note that not all genetic variants will result in the same symptoms or to the same degree in different individuals; this is known as variable expressivity.⁷ 

Role of genetics in paediatric cardiomyopathy

What are genes?

Imagine genes as the set of instructions for baking a cake. Each ingredient needed for the cake is a gene, and if you have the wrong ingredients, or too much or too little of any single ingredient, you will not get the cake you intended to bake in the first place. Similarly, a mutation in a gene can alter its subsequent function. Such mutations can be inherited from parents – for example in an autosomal dominant or an autosomal recessive pattern (from just one parent or both of them) – whilst some may be completely new de novo mutations which occur during development.⁸ 

Another key term to be familiar with is pathogenic variant (PV), which is the term used to describe an alteration in a specific gene that has been known to cause disease. This information can be extracted from previous diagnoses of patients, computational and functional data. There may be several different PVs present in an individual that can lead to the manifestation of CM in children, and symptoms are dependent on a variety of both genetic and environmental factors.³

Here are some examples of key mutations:

• Synonymous - a change in a single nucleotide base (singular ‘readable’ component making up a gene) that will code for the same amino acid (building block of proteins)
• Missense - a change in a single base that will code for a different amino acid
• Nonsense - stop codon is used, resulting in a shortened protein 
• Frameshift - either addition or deletion of bases not in multiples of three, resulting in a loss or gain of amino acids⁹

What are the inherited genes involved in pediatric CM?

As CM can be an autosomal dominant disorder, only one copy of a mutated gene inherited from either parent is sufficient for that child to be affected. In other words, there is a 50% chance of a child with at least one parent who is a carrier, to inherit the risk of having CM.³

De novo mutations, which are essentially new mutations that haven’t been inherited from either parent, can also lead to CM. This collectively contributes to the idea that there is an interplay of various genetic factors and possible environmental factors that can result in different types of CM and their inheritance.³

Whether the mutation will result in the disease being inherited also depends on penetrance. This is the proportion of individuals with a copy of the mutated gene that will be affected by the disease.

MYH7 - for force generation

The MYH7 gene encodes the slow myosin heavy chain, found in cardiac muscle. It is responsible for generating adenosine triphosphate (ATP) the molecular equivalent of energy, hence generating the mechanical function of the heart, and allowing for systole and diastole (action and rest phases of heart muscle contraction).¹⁰ 

For muscle contraction to occur, the thick (myosin) and thin (actin) sarcomere filaments must slide along one another, release calcium and allow for actin-myosin interaction.¹¹ However, a mutation in this particular gene results in faster actin-filament sliding, hence greater force production, which can be seen in HCM.¹¹ MYH7 can also result in DCM.

LMNA 

This is a common variant occurring in up to 10% of DCM cases. The LMNA gene codes for lamins A and C, structural proteins which are responsible for the mechanical support of the cell nucleus and allow for normal synthesis of DNA. This frailty found in the nuclear membranes may result in cellular death of cardiac muscle, hence weakening the heart as seen in DCM. Abnormalities of this gene can also result in heart failure and sudden cardiac death (SCD).¹² 

MYBPC3 - for structural changes and regulation 

This is the myosin binding protein-C, which interacts with actin and myosin to maintain the sarcomere layer. It also regulates the rate of muscle contraction and relaxation. It is the primary gene causing HCM and DCM.¹³ Pathogenic MYBPC3 is linked to a mild form of hypertrophy and late-onset manifestations in patients.³ Most of the mutations observed from MYBPC3 were frameshifts, which resulted in truncated protein or the absence of protein due to poor cellular quality.¹⁴

TTN - for structural changes 

TTN truncating variants are commonly seen in DCM, affecting around 20% of patients with this CM type.³ Titin is a large protein encoded by the TTN gene and has an integral function in providing forceful movements during muscle contraction. TTN is composed of four main subunits that are essential for the structural support of the sarcomere. It consists of the A band that acts as an anchor for myosin binding when muscle contraction occurs. The I band is responsible for the mechanical force of muscular contraction, whereas the M band and I band are vital in linking TNN to the sarcomere.¹⁵

Why is genetic testing important?

Genetic testing is the process of detecting family members who have inherited the disease-causing variant and are at risk of developing symptoms associated with the disease of interest.¹⁶ It is ideal to determine genetic risk and available options for prenatal genetic testing before pregnancy.¹² 

Genetic counselling will provide an opportunity to discuss the potential risks for children of carriers of the genetic mutations associated with CM, and gain better insight into the reproductive options that may be suitable for parents.¹² 

FAQs

How do I know if I will pass on CM to my children?

Evaluating your family history and identifying the occurrence of heart failure, DCM, heart transplants and the use of pacemakers throughout it can be indicative of the presence of genetic mutations associated with CM. As the most common inheritance pattern of CM is autosomal dominant, there will always be a 50% chance of a carrier of this disease, resulting in having an affected child. However, with advancing technologies, there are genetic counselling options available to allow for family planning and testing.³ 

Summary

Paediatric CM is predominantly influenced by genetic factors, because of its possible inheritance in an autosomal dominant pattern. This condition can manifest differently through various structural and functional abnormalities affecting the myocardium. Genetic testing can be used as a diagnostic test and as a screening procedure for people affected by this condition and their families.