Heart Disease and Genetic Testing: Who Should Be Tested and When?
Assoc. Prof. Sezen Bağlan Uzunget, MD
Cardiologist
Can Heart Disease Be Inherited?
Some cardiovascular diseases have a strong genetic component.
Common conditions such as coronary artery disease and hypertension result from a combination of genetic susceptibility, lifestyle, and environmental factors.
Other disorders, including certain cardiomyopathies, inherited arrhythmia syndromes, and thoracic aortic diseases, may be associated with disease-causing variants in specific genes.
In these conditions, genetic evaluation may help establish a diagnosis, guide treatment, and identify relatives who require screening.
Genetic testing is not necessary for every patient with heart disease. It should be guided by clinical findings and family history.
What Is the Difference Between Genetic Testing and Family Screening?
Genetic testing analyzes DNA, usually from a blood or saliva sample, to identify variants associated with inherited disease.
Family screening involves evaluating relatives for signs of cardiovascular disease using tests such as ECG, echocardiography, ambulatory rhythm monitoring, or cardiac MRI.
These approaches complement each other.
A negative genetic result in an affected patient does not necessarily eliminate the need for clinical screening of relatives.
When a pathogenic or likely pathogenic familial variant is identified, targeted testing can be offered to appropriate family members.
Who Should Be Considered for Cardiovascular Genetic Evaluation?
Genetic evaluation is particularly relevant for patients with:
- Hypertrophic cardiomyopathy
- Familial or unexplained dilated cardiomyopathy
- Suspected arrhythmogenic cardiomyopathy
- A family history of unexplained sudden cardiac death
- Suspected inherited arrhythmia syndromes
- Early-onset thoracic aortic aneurysm or dissection
- Suspected familial hypercholesterolemia
- Multiple relatives affected by a similar cardiovascular disorder
The appropriate genetic test depends on the suspected disease.
1. Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is characterized by otherwise unexplained thickening of the heart muscle.
Disease-associated variants are often found in genes encoding sarcomeric proteins, including MYH7 and MYBPC3.
Genetic testing should be considered in patients with established hypertrophic cardiomyopathy, particularly to clarify the diagnosis and facilitate family screening.
First-degree relatives should undergo appropriate clinical evaluation.
If a pathogenic familial variant is identified, targeted genetic testing may help distinguish relatives who require ongoing surveillance from those who do not carry that specific variant.
A negative genetic test does not exclude clinically diagnosed hypertrophic cardiomyopathy.
2. Dilated Cardiomyopathy
Dilated cardiomyopathy may involve enlargement of the cardiac chambers and impaired ventricular contraction.
Genetic evaluation is particularly important when there is:
- A family history of cardiomyopathy
- Unexplained ventricular dysfunction at a young age
- Sudden cardiac death in relatives
- Associated conduction disease
- Ventricular arrhythmias
- Suggestive cardiac MRI findings
Relevant genes may include TTN, LMNA, FLNC, DSP, and RBM20.
Some genetic findings can influence arrhythmic risk assessment and decisions about implantable cardioverter-defibrillator therapy.
However, the presence of a genetic variant alone does not automatically establish an indication for an ICD.
3. Arrhythmogenic Cardiomyopathy
Arrhythmogenic cardiomyopathy is associated with myocardial abnormalities and potentially serious ventricular arrhythmias.
It may involve the right ventricle, left ventricle, or both.
Genetic evaluation is especially relevant when characteristic imaging or ECG abnormalities occur alongside ventricular arrhythmias or a family history of sudden cardiac death.
Results may influence family screening, exercise recommendations, and clinical follow-up.
4. Family History of Sudden Cardiac Death
Unexplained sudden death, particularly at a young age, may indicate an inherited cardiomyopathy or arrhythmia syndrome.
Warning features include:
- Sudden death during exercise
- Unexplained death during sleep
- Unexplained drowning
- Multiple sudden deaths within a family
- Sudden cardiac arrest without an established cause
Evaluation may include ECG, echocardiography, ambulatory rhythm monitoring, exercise testing, cardiac MRI, and selected genetic tests.
When appropriate biological samples are available, postmortem genetic testing may also be considered.
A normal ECG does not exclude every inherited cardiac disorder.
5. Inherited Arrhythmia Syndromes
Inherited electrical disorders include:
- Long QT syndrome
- Brugada syndrome
- Catecholaminergic polymorphic ventricular tachycardia (CPVT)
- Short QT syndrome
- Certain inherited conduction disorders
Genetic testing may be appropriate when clinical findings strongly suggest one of these conditions or when a pathogenic familial variant has already been identified.
For example, recurrent exercise-related syncope or exercise-induced polymorphic ventricular arrhythmias may raise suspicion for CPVT.
However, a borderline QTc measurement alone is not an automatic indication for broad genetic testing.
Acquired causes, including medications and electrolyte abnormalities, should first be considered.
6. Thoracic Aortic Aneurysm and Dissection
Some thoracic aortic diseases are inherited.
Examples include Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, and nonsyndromic heritable thoracic aortic disease.
Genetic testing is particularly relevant in patients with:
- Thoracic aortic aneurysm or dissection at a young age
- A family history of thoracic aortic disease
- Features suggestive of a connective tissue disorder
- Unexplained sudden death in relatives
Genes such as FBN1, TGFBR1, TGFBR2, and ACTA2 may be evaluated when clinically appropriate.
Genetic findings can affect imaging surveillance, family screening, and surgical thresholds.
Not every mild aortic enlargement requires genetic testing.
7. Familial Hypercholesterolemia
Familial hypercholesterolemia is an inherited condition associated with elevated LDL cholesterol from an early age.
Clinical suspicion increases with:
- Untreated LDL cholesterol of 190 mg/dL or higher in adults
- Markedly elevated LDL cholesterol in children
- Premature coronary artery disease
- Multiple relatives with high LDL cholesterol
- Tendon xanthomas
Genetic testing may identify disease-associated variants in genes such as LDLR, APOB, or PCSK9.
An LDL level above 190 mg/dL does not by itself confirm a genetic diagnosis.
When familial hypercholesterolemia is diagnosed, cascade screening of relatives is important.
Early diagnosis allows preventive treatment to begin before cardiovascular complications develop.
8. Congenital Heart Disease
Some congenital heart defects are associated with genetic syndromes.
Genetic evaluation may be particularly useful when a congenital defect occurs with other abnormalities, developmental differences, or a strong family history.
However, every patient with an isolated atrial septal defect, ventricular septal defect, or bicuspid aortic valve does not require broad genetic testing.
Echocardiographic screening of first-degree relatives may be appropriate in families affected by bicuspid aortic valve disease.
9. Is Lipoprotein(a) a Genetic Risk Factor?
Yes.
Lipoprotein(a), or Lp(a), concentration is predominantly genetically determined.
Elevated Lp(a) increases the risk of atherosclerotic cardiovascular disease and calcific aortic valve stenosis.
However, DNA testing is usually unnecessary to assess Lp(a)-related risk.
Measuring Lp(a) in the blood is the preferred clinical approach.
Measurement at least once in adulthood is recommended, and testing relatives may be appropriate when markedly elevated Lp(a) is identified.
Who Should Be Tested First in a Family?
Whenever possible, genetic testing should begin with a family member who has a clearly established clinical diagnosis.
This person is known as the index case.
For example, if a pathogenic variant is identified in a patient with hypertrophic cardiomyopathy, relatives can undergo targeted testing for that specific variant.
This approach is generally more informative than ordering broad genetic panels for unaffected relatives without first establishing the familial cause.
How Are Genetic Test Results Interpreted?
Pathogenic or Likely Pathogenic Variant
A genetic change supported by sufficient evidence of disease association.
Depending on the condition, it may influence diagnosis, treatment, and family screening.
Variant of Uncertain Significance (VUS)
A genetic change whose relationship to disease has not been established.
A VUS is not proof that a person has inherited heart disease.
It should not independently determine decisions about ICD implantation, surgery, or predictive genetic testing in healthy relatives.
Negative Result
No relevant disease-associated variant was identified by the test.
A negative result does not exclude every inherited cardiovascular disorder.
Do Children Need Genetic Screening?
The appropriate age depends on the suspected disease.
Some inherited arrhythmia syndromes require evaluation early in childhood.
Children in families affected by hypertrophic cardiomyopathy may also need clinical screening during childhood.
Testing decisions should consider the familial diagnosis, identified variant, age, symptoms, and sporting activities.
There is no single screening age that applies to every inherited heart condition.
Should Everyone Have a Cardiovascular Genetic Panel?
No.
Routine broad genetic testing of asymptomatic people without a relevant family history or clinical indication is generally not recommended.
Unselected testing may produce uncertain results, unnecessary investigations, and inappropriate clinical decisions.
Pre-test counseling and expert interpretation are essential.
Can Genetic Testing Change Treatment?
In selected conditions, yes.
Examples include:
- Arrhythmic risk assessment in inherited cardiomyopathies
- ICD decision-making in selected patients
- Surgical thresholds in heritable thoracic aortic disease
- Medication and lifestyle recommendations in inherited arrhythmia syndromes
- Early LDL-lowering therapy in familial hypercholesterolemia
- Targeted screening of relatives
Genetic findings must always be interpreted together with the clinical phenotype.
When Should You Seek Cardiovascular Evaluation?
Medical evaluation is particularly important when there is:
- Unexplained sudden death in the family
- Recurrent unexplained syncope
- Syncope during exercise
- Familial cardiomyopathy
- Early-onset thoracic aortic aneurysm or dissection
- Markedly elevated LDL cholesterol
- Multiple relatives with similar heart disease
- A known pathogenic familial genetic variant
Exercise-related syncope, syncope associated with serious palpitations, or sudden severe chest pain may require urgent assessment.
Frequently Asked Questions
My father had a heart attack. Do I need genetic testing?
Not necessarily. A family history of premature heart attack should prompt cardiovascular risk assessment, including cholesterol and Lp(a) measurement. Genetic testing may be appropriate if familial hypercholesterolemia is suspected.
My mother has hypertrophic cardiomyopathy. Should I be screened?
Yes. First-degree relatives should be offered appropriate clinical screening and, when a pathogenic familial variant is known, targeted genetic testing.
My ECG is normal, but there has been sudden death in my family. Am I safe?
A normal ECG does not exclude all inherited heart diseases. Additional evaluation may be necessary.
Does a negative genetic test guarantee that I will not develop heart disease?
No. Genetic tests do not identify every inherited cause and cannot exclude all future cardiovascular disease.
Should my child have genetic testing?
This depends on the familial condition, identified genetic variant, and the child's age and clinical circumstances.
This article is provided for general educational purposes. Cardiovascular genetic testing and family screening should be individualized through clinical assessment, family history, appropriate cardiac investigations, and genetic counseling.