Cardiogenetics and Metabolic Disorders

The findings of large-scale human genomic studies have significantly advanced our understanding of the causes of congenital heart disease (CHD), heart development in the embryo and fetus, and the long-term comorbidities associated with CHD.

The following section introduces the manifestations of genetic cardiac disease, including both structural and functional disease, according to the typical age of presentation (neonates and infants [birth to 2 years]; toddlers, children, and adolescents [2 years to 16 years]; and adults).

Neonates and Infants

Two common manifestations of genetic cardiac disease during the first year of life are:

• structural heart disease

• cardiomyopathy (sometimes due to inborn errors of metabolism)

Structural Heart Disease

Approximately 20%−30% of CHD is attributable to genetic variations, including aneuploidy, copy-number variants, and single-gene variations. This percentage is expected to increase with further advances in genetic research.

(Source: Advances in the Understanding of the Genetic Determinants of Congenital Heart Disease and Their Impact on Clinical Outcomes. J Am Heart Assoc 2018.)

Aneuploidy refers to an abnormal number of chromosomes in a cell, including the presence of an additional chromosome, such as Down syndrome (trisomy 21), or the absence of a chromosome, such as Turner syndrome (monosomy X).

• Trisomy 21 is a classic example of aneuploidy associated with CHD. Approximately 50% of children with trisomy 21 have associated CHD. The most common abnormality is a complete atrioventricular septal defect, although other structural cardiac defects may occur. All children with trisomy 21 should be evaluated by a pediatric cardiologist at birth or shortly thereafter.

Copy-number variation refers to deletions or duplications of segments of chromosomes. A deletion of chromosome 22, referred to as 22q11.2 deletion syndrome, was one of the first copy-number variations linked to CHD. The deletion affects the development of the pharyngeal arches. Affected individuals may have hypocalcemia due to absence of the parathyroid glands, immunodeficiency due to thymic aplasia, characteristic facial features, and neurodevelopmental abnormalities. Common structural defects associated with this deletion include:

• tetralogy of Fallot

• truncus arteriosus

• interrupted aortic arch type B

Single-gene variants alter the nucleotide sequence of a particular gene and can either be inherited or de novo mutations. Single-gene variants account for both syndromic and nonsyndromic forms of CHD. The 2018 AHA Scientific Statement on the Genetic Basis for Congenital Heart Disease provides a list of genetic syndromes associated with CHD. The following are some representative examples:

• syndromic congenital heart disease associated with single gene variants include:

  • Alagille syndrome: This autosomal dominant condition is due to variations in the JAG 1 or NOTCH 2 genes and leads to cardiovascular, hepatic, orthopedic, and ophthalmologic complications. In terms of cardiac complications, two thirds of cases develop stenosis of the branch pulmonary arteries or other forms of arterial narrowing (aortic coarctation, renal artery stenosis, middle aortic syndrome, or narrowing of the cerebral arteries). Other associated structural cardiac lesions include atrial septal defect, tetralogy of Fallot, and ventricular septal defects.

  • RASopathies: This group of autosomal dominant disorders are caused by pathogenic variants in genes within the RAS/mitogen-activated protein kinase pathway. These disorders are associated with overlapping manifestations involving the cardiac, musculoskeletal, and neurologic systems.

    • Noonan Syndrome: Children with Noonan Syndrome have characteristic facial features, as well as complications of the endocrine, hematologic, lymphatic, neurologic, orthopedic, gastrointestinal, renal, and cardiovascular systems. Cardiac involvement includes hypertrophic cardiomyopathy, pulmonary valve stenosis, coarctation of the aorta, atrial septal defects, and arterial aneurysms (coronary, aortic, pulmonary, and intracranial).

  • Heterotaxy and ciliopathies: Cilia are critical organelles for cardiac development. During organogenesis, cilia establish left-right asymmetry and function in cardiac signaling. Variations in a number of genes can alter ciliary function and lead to different congenital malformations.

    • Heterotaxy syndrome is one condition that results from ciliary dysfunction: Organ placement deviates from the normal situs solitus or complete situs inversus arrangement and can include left or right atrial isomerism (two left or right atria). Associated congenital cardiac defects include atrioventricular septal defects (frequently unbalanced), anomalous pulmonary venous return, and various rhythm disturbances (i.e., absent sinus node in left atrial isomerism).

• Non-syndromic congenital heart diseases associated with single-gene variants include variations in genes that encode transcription factors, cell-signaling molecules, structural proteins, and adhesion molecules.

  • NKX2-5 gene: Mutations in this gene cause a number of different defects including atrial septal defects, ventricular septal defects, disorders of cardiac conduction as well as more complex forms of CHD (e.g., Tetralogy of Fallot, Ebstein malformation, congenitally corrected transposition, interrupted aortic arch, double outlet right ventricle, truncus arteriosus, hypoplastic left heart syndrome, and aortic coarctation).

Metabolic Disorders

The following information is summarized from a review of pediatric cardiomyopathy of metabolic genetic etiologies.

Inborn errors of metabolism (IEMs) account for 5% of pediatric cardiomyopathies. These conditions most often present during the immediate newborn period but may continue to present during the first 2 years of life. Cardiomyopathy may be the primary presenting symptom, or an incidental finding discovered as part of a routine multisystem evaluation. Identifying IEMs early is critical because they can be reversible with early treatment or fatal if not treated quickly.

Metabolic causes should be considered in any child presenting in the first year of life with cardiac failure or cardiomyopathy. The presentation is often acute during a routine childhood intercurrent illness and can be confused with viral myocarditis. Other times to consider an IEM are when cardiac disease is associated with other systemic symptoms such as hypotonia, developmental delay, macroglossia, or organomegaly. Unusual laboratory findings (e.g., severe lactic acidosis, hypoglycemia, hyperammonemia, unexplained anion-gap acidosis, liver failure, or an unusually high creatine kinase level) should also prompt consideration. Timely consultation with a metabolic geneticist is critical to guide workup and treatment if an IEM is under consideration.

IEMs can be classified as:

• substrate disorders: including fatty acid oxidation defects, carnitine transport disorders, organic acidemias, organic acidurias, and glycogen storage diseases

• organelle disorders: including peroxisomal, mitochondrial, and lysosomal storage disorders

The pathological effects of IEMs include bulk storage and infiltration of substrate that adversely affect the mechanics of cardiomyocyte function, lead to impaired energy production, and result in the production of toxic metabolites.

Pompe disease/glycogen storage disease type II is an example of an IEM that causes neonatal hypertrophic cardiomyopathy. It is an autosomal recessive disorder caused by acid alpha-glucosidase deficiency and can be classified into the following two subtypes:

• Classic infantile Pompe disease usually presents in the infantile period, although occasionally a child is diagnosed later in the first year. Neonates present with cardiac hypertrophy and severe hypotonia that may manifest as respiratory distress. They may also have an enlarged tongue and hepatomegaly. An ECG from an infant with severe hypertrophic cardiomyopathy is shown below. Early treatment with enzyme replacement therapy usually results in reversal of cardiac hypertrophy.

• Late-onset Pompe disease (LOPD) is not associated with the hypertrophic cardiomyopathy seen in the classic infantile form.

Electrocardiogram of an infant with Pompe disease showing severe left ventricular hypertrophy with repolarization abnormalities (courtesy of the authors).

For more information on metabolic disorders, see the section on Metabolic Disorders in the Pediatric Genetic/Metabolic Disorders rotation guide.

Toddlers, Children, and Adolescents

The most common presentations of genetic cardiac disease in toddlers, children, and adolescents are:

• aortopathy

• cardiomyopathy

• inherited arrhythmias (see Arrhythmia in this rotation guide)

Knowledge of genetic mutations that lead to structural heart disease (described above) is also important for evaluation of toddlers and adolescents because these mutations often cause other comorbidities that become evident during this time period.

Aortopathy

Aortopathies are connective tissue disorders that lead to progressive dilation of the aorta and increase risk for aortic dissection. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) joint guidelines address monitoring and intervention for aortic dilation in patients with genetic aortopathies.

Genetic syndromes associated with aortic dilation include:

• Marfan syndrome

• Loeys-Dietz syndrome

• Turner syndrome

• Ehlers-Danlos syndrome type IV

• arterial tortuosity syndrome

(Source: 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients with Thoracic Aortic Disease. Circulation 2010.)

Cardiomyopathy

Types of inherited cardiomyopathies include:

• Hypertrophic: Patients with hypertrophic cardiomyopathy (HCM) develop thickening of the heart muscle that causes impaired diastolic filling and can be complicated by fatal arrhythmias.

• Dilated: Patients with dilated cardiomyopathy develop dilation and dysfunction of the left ventricle that limits cardiac output.

• Restrictive: Restrictive cardiomyopathy causes impaired diastolic relaxation of the ventricles that limits both preload and cardiac output.

• Arrhythmogenic: Arrhythmogenic cardiomyopathy encompasses forms of cardiomyopathy that involve structural changes in the myocardium that predispose patients to potentially fatal arrhythmias. An example of this is arrhythmogenic right ventricular cardiomyopathy.

• Left ventricular noncompaction: Left ventricular noncompaction (LVNC) cardiomyopathy is the rarest form of cardiomyopathy. It is a disease of endomyocardial trabeculations that increase in number and prominence and carries a high risk of malignant arrhythmias, thromboembolic phenomenon, and left ventricular dysfunction. Imaging shows a characteristic appearance in left ventricular noncompaction cardiomyopathy Bilayered myocardium with prominent trabeculations can be seen in children with LVNC as a result of arrest in compaction during embryonic development.

Familial hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies, occurring in an estimated 1 in 500 individuals. HCM is predominantly due to genetic mutations in sarcomeric proteins. Affected persons rarely present before age 12 years. The diagnosis may be made by an echocardiogram or cardiac MRI demonstrating a hypertrophied and nondilated left ventricle in the absence of another cardiac or systemic disease capable of producing left ventricular hypertrophy. Genetic testing is useful in identifying pathogenic mutations that can be used to screen asymptomatic, phenotype-negative family members. Patients may present with exercise intolerance, syncope, chest pain, or palpitations. HCM is also one of the more common causes of athlete sudden death. Tachycardia and conditions that decrease left ventricular preload can lead to dynamic obstruction of the left ventricular outflow tract and cause an acute decrease in cardiac output. For this reason, affected patients are often treated with medications (such as beta-blockers or calcium-channel blockers) to blunt their heart rate response to activity and are restricted from competitive sports. Complications of HCM include ventricular arrhythmia (leading to sudden cardiac death), heart failure, and pulmonary hypertension. The ACCF/AHA has published guidelines for the diagnosis and management of familial HCM.

Neurodevelopmental Disability in Patients with Genetic Congenital Heart Disease

Children with CHD are at increased risk of developmental disorder or disability or developmental delay. The genes that affect developmental pathways and lead to cardiac malformations often affect other critical developmental pathways (e.g., neurologic, renal, pulmonary) and can cause noncardiac comorbidities. Neurodevelopmental disability is a significant comorbid condition that is often present in patients with genetic CHD. The AHA guidelines for neurodevelopmental screening in children with CHD recommend more-intensive cognitive and developmental screening in children with CHD due to genetic mutations associated with developmental disabilities, in order to facilitate early intervention services.

Adult Congenital Heart Disease

Genetic CHD not only affects long-term outcomes in patients but also increases the risk of recurrent CHD in future offspring.

Long-term outcomes: Adults with congenital heart disease (ACHD) have higher morbidity and risk of premature death than age-matched healthy peers. Comorbidities include dysfunction of the pulmonary, renal, and neurologic systems, and cancer. Genetic factors as well as the gene-environment interaction are thought to play an important role in the occurrence of comorbidities in ACHD patients.

Risk in future offspring: CHD in the general population occurs in approximately 1% of all live births. The risk of CHD increases to 2%-4% in a fetus with a parent or sibling affected by CHD without a known genetic cause. When a genetic etiology of the CHD defect in the affected family member is known, the risk of CHD in the patient's children depends on whether the defect is dominant or recessive and whether the disorder is fully penetrant.

Genetic Testing in Patients with Structural Heart Disease

Genetic testing of newborns with CHD is increasingly recommended and is considered standard of care in some centers, given our improved understanding of the genetics of CHD and the increasing sophistication and availability of genetic testing. Referral to a geneticist with expertise in cardiac disease should be considered in the following scenarios:

• an identified or suspected genetic condition

• a concerning family history for a hereditary syndrome

• as follow up to abnormal genetic-testing results

A proposed strategy for clinical genetic testing in CHD can be found here. For more information on genetic testing, see Genetic Variants and Testing in the Pediatric Genetic and Metabolic Disorders rotation guide.

Effect of Genetic Testing on Outcomes in CHD

Understanding the genetic etiology of CHD in a patient assists clinicians in determining the risks of peri-operative complications, neurodevelopmental outcomes, as well as long-term morbidity and mortality. The following table illustrates the known effect of genetic variations on patient outcomes:

(Source: Advances in the Understanding of the Genetic Determinants of Congenital Heart Disease and Their Impact on Clinical Outcomes. J Am Heart Assoc 2018.)