Hereditary cardiac pedigree: cardiogenetics family history in practice

Short version. Inherited cardiac conditions span cardiomyopathies, channelopathies, and aortopathies. A detailed three-generation pedigree — with careful attention to sudden unexplained deaths, drownings, unexplained accidents, early heart attacks, and any diagnosed cardiac condition — is one of the most useful tools for triaging who needs cardiogenetics referral and for narrowing the differential once the patient is in clinic. Most familial cardiomyopathies and channelopathies are autosomal dominant with variable expressivity and reduced penetrance, which means the pedigree pattern matters as much as any single individual's features. This guide walks through the landscape, the red flags, and how Evagene supports cardiac pedigree analysis.

The landscape of inherited cardiac conditions

Inherited cardiac conditions cluster into three broad categories and several overlap groups.

Cardiomyopathies

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, typically autosomal dominant, with more than a dozen sarcomeric genes implicated — most commonly MYBPC3 and MYH7. It is a leading cause of sudden cardiac death in young people, particularly during exertion, and can be present with minimal or no symptoms until a first event.

Dilated cardiomyopathy (DCM) is aetiologically heterogeneous: a substantial minority of cases are familial, with autosomal dominant inheritance most common, and a long list of implicated genes including TTN, LMNA, MYH7, and RBM20. Clinical presentation ranges from asymptomatic through heart failure to sudden death.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) — sometimes grouped as arrhythmogenic cardiomyopathy when left-dominant or biventricular forms are considered — is autosomal dominant and typically associated with variants in desmosomal genes (PKP2, DSG2, DSC2, JUP, DSP). It presents with ventricular arrhythmia and right ventricular dysfunction, often during exertion.

Left ventricular non-compaction (LVNC) and several rarer cardiomyopathy subtypes round out the category.

Channelopathies

Long QT syndrome (LQTS) is a prolonged ventricular repolarisation syndrome carrying risk of torsades de pointes and sudden death. It has multiple subtypes associated with different potassium or sodium channel genes (KCNQ1, KCNH2, SCN5A, among others) and is predominantly autosomal dominant.

Brugada syndrome is a sodium-channel disorder classically associated with SCN5A variants, presenting with a characteristic ECG pattern and risk of polymorphic ventricular tachycardia and sudden death, often at rest or during sleep.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) presents with exercise- or emotion-induced ventricular arrhythmia in structurally normal hearts, typically in childhood or adolescence, with autosomal dominant (RYR2) and autosomal recessive (CASQ2) forms.

Short QT syndrome completes the main channelopathy set.

Aortopathies and connective tissue disorders

Marfan syndrome is an autosomal dominant connective tissue disorder caused by variants in FBN1, characterised by aortic root dilatation, tall stature with disproportionate limbs, and ocular involvement. Risk of aortic dissection drives surveillance and management.

Loeys-Dietz syndrome is a group of autosomal dominant aortopathies associated with TGF-β pathway genes (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3), often with earlier and more distal vascular involvement than Marfan.

Vascular Ehlers-Danlos syndrome (COL3A1), familial thoracic aortic aneurysm and dissection (multiple genes), and bicuspid aortic valve-associated aortopathy complete the category.

Overlap and related conditions

Familial hypercholesterolaemia (LDLR, APOB, PCSK9) is autosomal dominant and causes early-onset atherosclerotic coronary artery disease, with family histories of heart attacks before 55 often reflecting underlying FH. Amyloidosis, particularly transthyretin amyloid cardiomyopathy, and Fabry disease (X-linked) are important mimics of other cardiomyopathies.

Red flags in the family history

The single most useful question in many cardiac history-takings is: has anyone in the family died suddenly and unexpectedly? The follow-up questions — when, how, at what age, and under what circumstances — often reveal a pattern that routine questioning misses.

• Sudden unexplained death before 40. Includes witnessed collapse and death, unwitnessed deaths attributed to "heart attack" without confirmation, and deaths labelled at autopsy as undetermined or sudden adult death syndrome (SADS). These often reflect unrecognised channelopathies or cardiomyopathies.
• Unexplained drowning, particularly in good swimmers. Long QT subtype 1 is associated with swimming-triggered events.
• Unexplained single-vehicle motor accidents. A small but real proportion may reflect arrhythmic events rather than straightforward accidents.
• Sudden infant death syndrome. A small fraction of cases have been linked to channelopathy variants in post-mortem molecular autopsies.
• Unexplained seizures. Arrhythmic syncope can be misdiagnosed as epilepsy when the rhythm disturbance is not captured.
• Cardiac arrest during exertion. Arrhythmogenic cardiomyopathy, HCM, and CPVT are all associated with exertional events.
• Cardiac arrest during sleep or rest. Brugada syndrome and some long QT subtypes present with rest-associated events.
• Early heart attacks before 55. Familial hypercholesterolaemia and related conditions.
• Established diagnosis in a relative. Cardiomyopathy, channelopathy, aortic aneurysm or dissection, Marfan or related syndrome, or an implanted defibrillator in a first- or second-degree relative.
• Pacemaker or defibrillator in youth. A young relative with a device often points to an inherited condition even when the family no longer knows the name.

Each of these flags deserves explicit recording on the pedigree. Evagene's structured data model captures age at event, cause of death where known, and family narrative in a free-text field alongside the structured diagnosis.

The cardiogenetics clinic workflow

A cardiogenetics clinic combines cardiology and clinical genetics. A typical workflow starts with a detailed three-generation pedigree — constructed from the patient's account, relatives' contributions, and any existing records — and moves through phenotyping and molecular testing.

• Pedigree construction. Three generations, with explicit recording of the red flags above, ethnic origin of all four grandparents, and any consanguinity.
• Cardiac phenotyping. ECG, echocardiogram, cardiac MRI in selected cases, exercise testing, Holter monitoring; the specific set depends on the differential.
• Pre-test counselling. Discussion of what testing can and cannot do, implications for insurance (in some jurisdictions), implications for relatives, and informed consent.
• Molecular testing. Targeted gene panels are common, with exome or genome sequencing in selected cases. Panel choice depends on the clinical diagnosis.
• Variant interpretation. Variants are classified using ACMG criteria; a variant of uncertain significance benefits from segregation analysis in the family, which the pedigree supports directly.
• Cascade testing. Once a pathogenic variant is identified, predictive testing is offered to at-risk relatives, with appropriate counselling.
• Surveillance and management. Ongoing cardiology care for affected and at-risk individuals, tailored to the specific condition.

The pedigree sits at the centre of all of this. It drives the referral decision, the testing strategy, the variant interpretation, and the cascade testing plan.

Inheritance patterns and what the pedigree tells you

Most familial cardiomyopathies are autosomal dominant. An affected parent transmits the variant to half their children on average; each carrier child has a risk of developing the phenotype that depends on penetrance for the specific variant and gene.

Variable expressivity — the same variant causing different clinical pictures in different relatives — is the norm in most cardiac Mendelian conditions. One carrier may have dramatic disease in childhood; another, in the same family with the same variant, may be asymptomatic at 60. Interpreting the pedigree requires holding this in mind.

Reduced penetrance — some carriers never developing the phenotype — is also common, particularly in channelopathies. A pedigree with two affected individuals and an unaffected carrier parent between them is not unusual.

Autosomal recessive patterns appear in specific conditions (Jervell and Lange-Nielsen syndrome for long QT with sensorineural deafness, CPVT with CASQ2 variants, some mitochondrial cardiomyopathies with nuclear-encoded autosomal recessive inheritance). A consanguineous family history or two affected siblings with unaffected parents are key signals.

X-linked inheritance applies in Fabry disease, Danon disease, and Emery-Dreifuss muscular dystrophy with cardiac involvement. Male predominance and absence of male-to-male transmission are key pedigree features.

Evagene's Mendelian inheritance calculator computes carrier and affection probabilities across the pedigree for autosomal dominant, autosomal recessive, and X-linked recessive inheritance, which supports quick analysis of cardiac pedigrees before or instead of formal cardiogenetic referral.

Surveillance and cascade testing: the pedigree as a working document

Once a variant or clinical diagnosis is established in a family, the pedigree becomes a surveillance plan. First-degree relatives of an affected individual in an autosomal dominant condition are at 50% a priori risk. Once their genotype is known, risk is resolved to essentially 0% (non-carrier) or up to 100% penetrance-adjusted (carrier). Periodic cardiology review — ECG, echocardiogram, sometimes MRI — becomes the standard of care for those at risk.

The cascade testing process is best organised around the pedigree itself. Mark each relative's testing status on the diagram, note the date, and track who has been informed and offered testing. This is a clinical workflow artefact as much as a diagnostic tool, and a good cardiac pedigree platform should support it.

How Evagene supports cardiac pedigrees

Evagene's curated disease catalogue of over 200 conditions includes the major inherited cardiac conditions — HCM, DCM, ARVC, LVNC, LQTS, Brugada syndrome, CPVT, Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, familial thoracic aortic aneurysm, and familial hypercholesterolaemia — keyed to ICD-10 and OMIM, with standard inheritance patterns defined. Each individual in a pedigree can be annotated with a confirmed diagnosis, an inferred phenotype, carrier status, device status, and age at event.

Evagene's AI interpretation engine, driven by bring-your-own-key LLMs (Anthropic Claude, OpenAI GPT), can be prompted to review a cardiac pedigree for the red flags listed above — sudden deaths, drownings, unexplained accidents, clustering of cardiomyopathy or channelopathy, affected generations — and surface a structured interpretation that a clinician can use as a drafting aid for the clinic letter. Analysis Templates let a service codify its house style so cardiac-specific prompts can be reused across cases without prompt engineering each time.

The Mendelian inheritance calculator supports autosomal dominant, autosomal recessive, and X-linked recessive inheritance patterns for cardiac conditions where Bayesian cancer-specific models (BRCAPRO, MMRpro, PancPRO) do not apply. Batch risk screening can sweep the pedigree against the full disease catalogue with configurable thresholds, which is useful when a pedigree has features that could point in several cardiac directions.

Frequently asked questions

Related reading

• Rare disease pedigree software
• Mendelian inheritance calculator
• Clinical genetics pedigree tool
• Batch pedigree risk screening
• Hereditary cancer risk assessment
• Pedigree drawing software