Familial and Genetic Screening in Premature Cardiovascular Disease

Definition and scope

Familial and genetic screening in cardiovascular medicine is the systematic assessment of relatives and other individuals who may carry an inherited predisposition to cardiovascular disease. It combines a structured family history, clinical evaluation, cardiac investigations, genetic counselling and, where appropriate, molecular testing.

The approach is particularly relevant to cardiomyopathies, channelopathies, heritable aortopathies, selected congenital heart diseases, pulmonary arterial hypertension and thromboembolic disorders. Most recognised heritable cardiovascular conditions demonstrate autosomal-dominant transmission, in which an affected heterozygous individual has a 50% risk of transmitting the relevant variant to each child. However, other inheritance patterns, de novo variants, incomplete penetrance and variable phenotypic expression complicate risk prediction.

Familial clustering may also reflect shared environmental or behavioural factors rather than a single-gene disorder. This distinction is important in premature coronary disease, hypertension, type 2 diabetes and hyperlipidaemia, which are usually polygenic conditions, although family history remains clinically useful for estimating risk.

Pathophysiology and genetic principles

Penetrance and variable expression

A pathogenic variant does not invariably result in clinical disease. Penetrance is incomplete and age-dependent, and the severity and manifestations of disease may differ substantially among carriers. Consequently, a normal examination or cardiac investigation at one point in time does not reliably exclude future disease in an at-risk relative.

Across inherited cardiomyopathies, phenotypic expression generally follows a sigmoid pattern over the lifetime. Expression is relatively uncommon in the first decade, rises progressively through adulthood and becomes less steep in later life, although diagnoses may still occur after the age of 65 years. Overall penetrance in cardiomyopathy families may reach 70–90% by age 70 years. In hypertrophic cardiomyopathy (HCM), expression may occur more rapidly during childhood and early adulthood; male sex, subtle electrocardiographic abnormalities and particular genes may predict earlier disease expression. In many cardiomyopathies, women manifest disease later than men, with the timing shifted by approximately 10 years in some studies.

Inheritance patterns

Autosomal-dominant inheritance is predominant in many cardiomyopathies and channelopathies. Nevertheless, apparently sporadic disease may result from:

• Incomplete penetrance of a variant inherited from a parent.

• A de novo variant.

• Less commonly, autosomal-recessive inheritance.

• X-linked or other non-autosomal-dominant mechanisms.

• Complex or multifactorial genetic architecture.

The inheritance pattern affects the appropriate scope and duration of family surveillance. For example, heterozygous carriers in a clearly recessive cardiomyopathy may not require the same follow-up as individuals at risk in an autosomal-dominant family, whereas heterozygous carriers of an X-linked condition may develop a phenotype later and require delayed or individualized assessment.

Disease-specific genetic architecture

HCM is predominantly associated with variants affecting sarcomeric proteins, particularly MYH7 and MYBPC3. Approximately 40–60% of tested patients have a single variant identified as the cause of disease, although the yield varies by cohort. A causative variant is more likely to be found in a young patient with a clear family history and less likely in an older patient with non-classical features.

Dilated cardiomyopathy (DCM) has a substantially more diverse genetic basis. Pathogenic or likely pathogenic variants in relevant DCM genes were identified in approximately 22% of cases in one large study, while variants of uncertain significance were found in a further 44%. Truncating variants in TTN are among the most frequent recognised genetic findings and account for approximately 10–20% of cases, depending on the population studied. Other genes may contribute much smaller proportions of cases.

Some genetic disorders mimic a conventional cardiomyopathy phenotype. These “genocopies” are clinically important because they may differ in inheritance risk, prognosis and treatment. In HCM, less than 5% of adults and up to 25% of children may have a causative variant in a gene associated with a phenocopy. Childhood HCM has a broader aetiological spectrum, including inborn errors of metabolism, malformation syndromes and neuromuscular disorders; sarcomeric disease remains the most common cause outside infancy.

Clinical presentation and symptoms

The relatives of patients with inherited cardiovascular disease may be:

• Clinically affected and symptomatic.

• Clinically affected but asymptomatic.

• Genetically affected without an established phenotype.

• Temporarily phenotype-negative but still at risk because of age-related penetrance.

• Truly unaffected and not genetically predisposed.

Cardiomyopathies

DCM commonly has a prolonged clinically silent phase. The first overt manifestation may be symptomatic heart failure, an arrhythmia or an embolic event. Clinically detectable disease may also be discovered incidentally during routine or pre-procedural assessment, often after subtle ECG abnormalities prompt echocardiography.

HCM may remain clinically silent until adolescence or adulthood, and symptoms or signs can emerge in early or middle adulthood or later. The source material does not provide a detailed symptom profile or physical examination findings for HCM; however, its clinical relevance in family screening lies in the possibility of delayed presentation and serious outcomes, including sudden death and symptomatic heart failure.

Arrhythmogenic cardiomyopathy may be identified before symptoms through family evaluation and genetic testing. Family screening may also contribute to arrhythmic risk stratification.

Premature atherosclerotic cardiovascular disease

Premature cardiovascular disease generally denotes clinical disease occurring before age 65 years in women or before age 55 years in men. A family history of premature cardiovascular disease is associated with increased risk in offspring and is used as a risk-enhancing factor when considering preventive treatment in adults with borderline or intermediate risk.

Evaluation and physical examination

Family history

A multigenerational family history is the foundation of evaluation. It should ideally be recorded as a pedigree and should include:

• The structure of the family.

• Cardiovascular diagnoses.

• Sudden deaths.

• Heart failure.

• Arrhythmias.

• Embolic events.

• Ages at disease onset.

• Ages and causes of death.

• Individuals who have undergone cardiac investigations or genetic testing.

• Ethnic or geographic factors when relevant to interpretation.

A family history spanning at least three generations is recommended in genetic cardiomyopathy assessment. The process helps determine whether disease is familial, suggests the likely inheritance pattern and identifies relatives who may require assessment.

A history of only one affected individual does not exclude a genetic cause. Sporadic HCM may reflect incomplete penetrance or a de novo variant, and sporadic DCM may also have an underlying genetic basis.

Clinical assessment

All first-degree relatives of patients with cardiomyopathy should be offered clinical screening with ECG and cardiac imaging, using echocardiography and/or cardiovascular magnetic resonance (CMR). The precise programme should be individualised according to:

• Age.

• Cardiomyopathy subtype.

• Family history.

• Inheritance pattern.

• Age at disease onset in affected relatives.

• Severity and complications in the family.

• Genotype and expected penetrance.

• Presence of abnormalities on previous assessments.

Physical examination forms part of clinical screening, particularly when genetic testing is unavailable or not pursued, although the source material does not specify examination findings or a detailed examination protocol.

Diagnostic strategy

Initial assessment of the proband

The affected or index patient should undergo comprehensive clinical evaluation before family testing is undertaken. The diagnostic work-up should establish the phenotype, assess for secondary findings and determine whether the presentation is compatible with a monogenic disorder.

For HCM, diagnostic genetic testing is most informative when the phenotype is characteristic, the patient is young or there is a strong family history. In childhood, a thorough assessment is particularly important because the phenotypic differential diagnosis is broader and includes metabolic, malformation and neuromuscular disorders.

Clinical screening of relatives

Clinical screening consists principally of:

• Physical examination.

• Twelve-lead ECG.

• Echocardiography.

• CMR when appropriate.

• Holter monitoring or other additional investigations guided by age, genotype and family phenotype.

A normal one-time evaluation has limited exclusionary value in a condition with age-related penetrance. Relatives who are initially phenotype-negative may therefore require longitudinal surveillance.

Genetic testing

Genetic testing should be performed in a multidisciplinary setting with expertise in:

• Genetic counselling.

• Testing methodology.

• Sequence-variant interpretation.

• Clinical application of results.

• Pre- and post-test counselling.

First-line testing should focus on genes with robust evidence for association with the presenting phenotype. If no cause is found but the suspicion of a monogenic disorder remains high, more extensive sequencing or analysis may be considered according to the family structure and clinical context.

Genetic testing in an affected individual may provide direct benefit by:

• Supporting or confirming the diagnosis.

• Informing prognosis.

• Influencing treatment selection.

• Clarifying reproductive options.

• Identifying relatives who require surveillance.

• Preventing unnecessary lifelong screening in relatives who are shown not to carry the familial variant.

A test may remain useful even when it is unlikely to alter the proband’s own management, because a molecular diagnosis may substantially alter the evaluation of relatives.

Variant interpretation

Variant classification determines whether cascade testing can be offered. If a pathogenic or likely pathogenic variant is identified in the affected individual, relatives may undergo focused testing for that specific variant.

A variant of uncertain significance should not be used for predictive testing in healthy relatives. Segregation analysis may nevertheless be undertaken in selected affected individuals or in parents to help determine whether the uncertain variant is pathogenic. Family members must be informed that such testing is intended to clarify variant interpretation rather than establish a diagnosis.

Variant classification should be reassessed periodically because changes in interpretation may alter family-screening recommendations.

Biomarkers and laboratory findings

The source material does not provide specific biomarker or laboratory-testing recommendations for familial and genetic screening. The principal screening investigations described are clinical assessment, ECG and cardiac imaging, supplemented by Holter monitoring or other investigations when indicated.

Management of genetically at-risk relatives

Genotype-positive, phenotype-positive relatives

Relatives who carry the familial pathogenic variant and have a clinical phenotype should receive phenotype-based management. The source material states that treatment should be based on the expressed phenotype, but does not provide detailed drug regimens, device criteria or disease-specific treatment algorithms.

These individuals should undergo ongoing clinical evaluation, generally including ECG, multimodality imaging and additional testing guided by their age, genotype and family phenotype. They should also receive counselling concerning the possibility of transmitting the variant to offspring.

Genotype-positive, phenotype-negative relatives

A carrier of a familial pathogenic variant remains at risk because penetrance and the timing and severity of expression cannot be predicted reliably. A normal current evaluation therefore does not eliminate the need for surveillance.

Serial follow-up should usually include ECG and cardiac imaging. Additional investigations, such as Holter monitoring, should be selected according to age, family phenotype and genotype. Surveillance extends from childhood through older age in families with cardiomyopathy-associated pathogenic or likely pathogenic variants.

Genotype-negative relatives

A relative who does not carry the established familial pathogenic variant and has no clinical phenotype can generally be reassured that neither they nor their children are at increased risk of developing the familial cardiomyopathy. Such individuals can usually be discharged from routine longitudinal screening, with advice to seek reassessment if symptoms develop or if clinically relevant new information emerges in the family.

This reassurance applies only when the familial variant has been established with sufficient confidence and the relative has undergone appropriate focused testing. It does not apply when the proband has only a variant of uncertain significance or when no causal variant has been identified.

Relatives in genotype-negative or untested families

When the proband has no identified pathogenic or likely pathogenic variant, or genetic testing has not been performed, predictive genetic testing is not available. Serial clinical evaluation is then the only strategy for relatives at risk.

Clinical screening generally begins with first-degree relatives and expands to additional relatives when new diagnoses are made. In families with no known disease-causing variant, children should receive ongoing surveillance because of age-related penetrance. Adult surveillance should be determined by family history and other risk factors.

When only one affected individual is identified and no genetic variant is found, the frequency and duration of follow-up may be reduced. If a comprehensive evaluation of the proband and an informative family pedigree indicates that the cardiomyopathy is isolated, discontinuation of periodic surveillance may be considered in first-degree relatives aged 50 years or older who have consistently normal cardiac investigations.

Screening schedules

No single interval applies to all families. The following schedules synthesise the intervals described for cardiomyopathy families.

Screening may begin earlier than routine schedules when there is a history of early-onset HCM, particularly severe family outcomes or substantial parental concern. In familial HCM, assessment of children may begin at diagnosis of the proband and generally no later than puberty, although earlier evaluation is appropriate in higher-risk circumstances.

Reproductive counselling

A confirmed familial pathogenic variant has implications for reproductive planning. Options include:

• Prenatal testing during an ongoing pregnancy using amniocentesis or chorionic villus sampling.

• Preimplantation genetic testing following in vitro fertilisation, with implantation of embryos lacking the familial pathogenic variant.

Pre-pregnancy genetic counselling should occur in a specialised cardiogenetic centre or an appropriately connected multidisciplinary network. Counselling should address transmission risk, variable expression, limitations of prediction and the medical and psychological implications of testing.

Genetic counselling and practical considerations

Genetic counselling is required before and after testing. It should explain:

• The possibility of a positive, negative or uncertain result.

• The distinction between a pathogenic variant and a variant of uncertain significance.

• The limitations imposed by incomplete penetrance.

• The inability to predict reliably when disease will develop or how severe it will be.

• The implications for children and other relatives.

• The effect of results on surveillance.

• Reproductive options.

• Potential psychological consequences.

Testing should be offered in a manner that recognises the burden of prolonged surveillance. A definitive familial diagnosis can spare genotype-negative relatives and their children from unnecessary longitudinal screening, whereas unresolved genetic risk necessitates continued clinical assessment.

Broad population screening for cardiomyopathy-associated genes and opportunistic analysis of cardiac genes identified during testing for another indication currently lack sufficient evidence to establish a favourable balance of benefit and harm. Such approaches should therefore be restricted to research settings unless the clinical context and local recommendations support otherwise.

Family screening in premature atherosclerotic cardiovascular disease

Family history is a routine component of preventive cardiovascular assessment. A maternal or paternal history of cardiovascular disease is associated with approximately a 1.5- to 2-fold increase in risk among offspring, with particularly high risk when disease occurred in the mother before age 50 years or in the father before age 55 years.

A family history of premature atherosclerotic cardiovascular disease is a risk-enhancing factor that may support initiation or intensification of statin therapy in adults with borderline or intermediate estimated risk. International guidance also considers premature atherosclerotic cardiovascular disease or genetic dyslipidaemia in the family an indication for assessing lipids and other risk factors, and a relative indication for measuring lipoprotein(a).

Monogenic risk variants can produce severe disease in classic Mendelian patterns. Examples relevant to cardiovascular practice include variants in LDLR, APOB and PCSK9 causing familial hypercholesterolaemia. Cascade screening in affected families is an important part of evaluation.

Polygenic risk scores aggregate the effects of multiple common variants. They have been associated with subclinical disease and coronary events, with an approximate 1.5-fold increase in risk per standard-deviation increase in score in the cited data. However, their incremental predictive value beyond standard risk factors has generally been marginal, their applicability is limited by ancestry representation and their cost-effectiveness remains uncertain. Their role in routine primary prevention therefore remains unresolved.

Guideline recommendations

The principal recommendations are:

• Obtain a detailed family history, preferably covering at least three generations and documenting disease events and ages of onset or death.

• Offer ECG and cardiac imaging to all first-degree relatives of patients with cardiomyopathy.

• Offer cascade genetic testing to relatives when a definitive pathogenic or likely pathogenic familial variant has been identified.

• Perform cardiomyopathy genetic testing in a multidisciplinary setting with appropriate expertise in counselling and variant interpretation.

• Use phenotype-focused first-line genetic testing, with broader analysis when clinical suspicion remains high despite an unrevealing initial test.

• Do not use a variant of uncertain significance for predictive testing in unaffected relatives.

• Continue clinical surveillance in relatives whose risk cannot be resolved genetically.

• Discharge genotype-negative relatives without a phenotype from routine surveillance in families with a confirmed causal variant, while advising reassessment if symptoms or new family information develops.

• Continue longitudinal evaluation of genotype-positive relatives, even when they are currently phenotype-negative.

• Individualise screening intervals according to age, disease subtype, genotype, family history, penetrance and complications.

• Offer ongoing surveillance from childhood to old age in carriers of cardiomyopathy-associated pathogenic or likely pathogenic variants and in relatives from families with established cardiomyopathy.

• Consider reproductive genetic options, including prenatal testing and preimplantation genetic testing, after appropriate counselling.

• Use family history of premature atherosclerotic cardiovascular disease as a risk-enhancing factor in preventive assessment and evaluate lipids and other relevant risk factors.

• Consider lipoprotein(a) measurement when premature atherosclerotic cardiovascular disease or genetic dyslipidaemia is present in the family.

• Restrict broad population or opportunistic cardiomyopathy gene screening to research contexts while the balance of benefits and harms remains insufficiently defined.

Prognosis and follow-up

The purpose of family screening is to identify disease before major complications develop and to permit timely initiation of appropriate management. Early recognition may help mitigate adverse outcomes, particularly sudden death and symptomatic heart failure.

Prognosis cannot be inferred solely from the presence or absence of a familial variant. Even among carriers, penetrance is variable and the timing and severity of expression are difficult to predict. Conversely, an initially normal phenotype does not necessarily indicate lifelong freedom from disease unless the individual has been shown not to carry the known familial pathogenic variant.

Follow-up should therefore be risk-based and longitudinal. Genotype-positive relatives require periodic ECG and imaging, with Holter monitoring or other investigations when indicated. Relatives in families without a resolved genetic cause require continued clinical assessment because a normal initial evaluation cannot reliably exclude future disease. Conversely, genotype-negative relatives from a genotype-positive family can generally be released from routine surveillance, reducing unnecessary medical and psychological burden.

The screening programme should be revisited when:

• A new family member develops cardiomyopathy.

• A sudden death, arrhythmia, heart failure or embolic event occurs.

• Variant classification changes.

• Additional genetic information becomes available.

• New abnormalities emerge on ECG, imaging or ambulatory monitoring.

• The family’s inheritance pattern becomes clearer.

A coordinated cardiogenetic service is therefore central to long-term management, integrating family history, phenotype, genotype, counselling, surveillance and reproductive planning over the lifetime of the family.