ICCnotes(beta)

Evidence-based clinical reference for inherited cardiac conditions, genetics, risk, treatment & guidelines

Genetic Testing

How to think about genetic testing in ICC

Genetic testing in inherited cardiac conditions is most useful when performed in an affected proband with a well-defined phenotype. The aim is not simply to "find a gene": it is to confirm a diagnosis, refine prognosis in selected conditions, enable cascade testing of relatives, and support reproductive counselling.[1]

Core principles
  • Establish the family pedigree first: a three-generation history including sudden deaths defines the proband, whether the disease is familial, and who is at risk
  • Test the most clearly affected person first (the proband), not an unaffected relative
  • Phenotype comes before genotype: the clinical syndrome should guide which test is chosen, not the reverse
  • Acquired causes and phenocopies must be excluded before an inherited diagnosis is assigned[1]

What a genetic test can and cannot answer

A genetic result changes management in some circumstances and not others; the table sets out, question by question, what a test can and cannot tell you.

Clinical questionA genetic test can…
Is this truly an inherited condition?support the diagnosis when a variant is found, but cannot replace phenotype as the central diagnostic anchor
Which gene or variant is responsible?identify the familial variant if the condition is monogenic, but cannot do so in polygenic or gene-elusive disease
Can relatives be tested?enable targeted testing of relatives once a P/LP variant is confirmed in the proband, but cannot be used to test relatives predictively before then
Does the result change risk stratification?change risk stratification for selected genes (e.g. LMNA, FLNC, DSP, PLN, RBM20, some LQTS genotypes), but cannot do so for most genes
What if the result is negative?lower clinical suspicion in some contexts, but cannot exclude inherited disease on its own, especially in genotype-negative HCM, DCM, Brugada syndrome and ACM/ARVC
What if the result is a VUS?flag a variant of interest for future reference, but cannot be used for predictive cascade testing[2]

The sequence continues through 1. What to Test, 2. Who to Test, 3. How to Test and 4. What to Do with Results; the appendices hold the variant, assay-method and glossary reference tables.

References & Review Date

Last reviewed: September 2026

  1. Musunuru K, et al. Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association. Circ Genom Precis Med. 2020;13(4):e000067. DOI: 10.1161/HCG.0000000000000067
  2. Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. DOI: 10.1038/gim.2015.30

Genetic basis by condition

Before considering genetic testing in your patient, it helps to know whether their condition is usually monogenic, usually complex/polygenic, or has major acquired phenocopies that must be excluded first.

ConditionMonogenic (Mendelian)Acquired / phenocopyComplex (likely polygenic)
Cardiomyopathies
ACM / ARVC~50–60% (desmosomal: PKP2, DSP, DSG2, DSC2, JUP; non-desmosomal DES, PLN, FLNC)Not a cause; cardiac sarcoidosis and myocarditis mimic the phenotype~40–50% gene-elusive, likely polygenic component
HCM~40–60% (sarcomeric, e.g. MYH7, MYBPC3)Not a cause; exclude hypertensive/athletic LVH, amyloid, Fabry~40–60% genotype-negative, increasingly polygenic
DCM~30–40% (up to ~50–60% with family history: TTN, LMNA, FLNC; DES in 1–2%)Common: myocarditis, alcohol, tachycardia-mediated, peripartum, chemotherapy, thyroidRemainder reflects polygenic susceptibility with environmental triggers
NDLVCOverlap genes (DSP, FLNC, DES, LMNA, TTN) in a share of cases; a heterogeneous umbrella group, so no reliable overall figureIncludes post-myocarditis scarThe non-monogenic remainder is itself heterogeneous, likely polygenic
RCMA minority (sarcomeric, desmin, hereditary ATTR)Commonest: AL amyloidosis, haemochromatosis, sarcoidosis, endomyocardial fibrosis, radiation, hypereosinophilic diseaseLimited; most non-genetic RCM has an identifiable cause
Channelopathies
LQTS~75–80% (KCNQ1/KCNH2/SCN5A = ~90% of genotyped)Acquired LQT (QT-prolonging drugs, hypokalaemia/hypomagnesaemia, bradycardia) is a separate, reversible entity~20–25% gene-elusive
CPVT~60% (RYR2 ~50–55%, CASQ2)No acquired CPVT, but its hallmark bidirectional VT has mimics (classically digoxin toxicity)~35–40% gene-elusive
Brugada syndromeOnly ~20–30% (SCN5A), the lowest of the channelopathiesPhenocopies: fever, drugs, electrolyte/metabolic disturbance~70% gene-elusive; oligogenic/polygenic with a structural substrate
SQTSA minority (gain-of-function KCNH2/KCNQ1/KCNJ2)Secondary short QT (hyperkalaemia, hypercalcaemia, acidosis, digoxin) is separate and reversibleMost cases gene-elusive; architecture incompletely defined
Storage & Metabolic
Fabry disease~100%, GLA variant causing α-galactosidase A deficiencyN/AN/A
Danon disease~100%, LAMP2 mutationN/AN/A
Pompe disease~100%, GAA mutations causing acid α-glucosidase deficiencyN/AN/A
Aortopathy & Connective Tissue
Marfan syndrome~100%, FBN1 variant (~25% de novo)N/AN/A
Loeys-Dietz syndromeClose to 100%, TGF-β pathway genes (TGFBR1/2, SMAD3, TGFB2/3)N/AN/A
Vascular Ehlers-Danlos syndromeClose to 100%, COL3A1 (rarely COL1A1), ~50% de novoN/AN/A
Bicuspid aortic valveA minority, familial/syndromic (e.g. NOTCH1)Not a cause (congenital malformation)The majority: multifactorial/polygenic; ~9–10% of first-degree relatives affected
Muscular Dystrophy & Neuromuscular
Duchenne/Becker muscular dystrophy~100%, DMD-gene mutations affecting dystrophin (~1/3 de novo)N/AN/A
Myotonic dystrophy~100%, DM1 (DMPK CTG expansion) and DM2 (CNBP CCTG expansion)N/AN/A
Friedreich ataxia~100%, biallelic FXN variants (nearly all GAA-repeat expansions)N/AN/A
Infiltrative
AmyloidosisHereditary ATTRv (TTR variants, e.g. V122I, T60A, V30M)AL (plasma-cell dyscrasia) and ATTRwt (age-related); ATTRwt is the commonest cardiac form in the elderlyNot a recognised mechanism
Mitochondrial
Mitochondrial diseaseMost known mitochondrial-disease genes are nuclear (Mendelian)Rare (e.g. some drug-induced mtDNA depletion)mtDNA point variants (maternal, heteroplasmic) and single large deletions (usually sporadic): monogenic but non-Mendelian, not polygenic

Within each group, conditions are listed by descending monogenic contribution. Green rows have a high (typically ≥50%) monogenic contribution: testing is high-yield once the phenotype fits, and a negative result is unusual enough to revisit (wrong gene tested, assay limitation, atypical variant type) rather than accept at face value. Amber rows have a lower yield but testing is still clearly indicated: in Brugada syndrome to enable cascade testing when a variant is found, and in cardiac amyloidosis to separate hereditary ATTRv from wild-type ATTRwt, which decides whether family screening is needed at all. Setting these expectations before ordering avoids over-reading a negative in a low-yield condition, or under-reacting to one in a high-yield condition.

References & Review Date

Last reviewed: September 2026

  1. Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194

Full per-condition citations for every figure above are on that condition's own Aetiology section.

Choosing the person to test

Eligibility is judged condition by condition against the Test Directory criteria below, but the first decision is who in the family is tested:

  1. Family history first. Take a three-generation pedigree, with specific enquiry about sudden deaths (Class 1)[6]. It identifies the proband and the relatives at risk
  2. Test the proband. The most clearly affected living person is tested against the eligibility criteria below. Relatives are not panel-tested before a familial variant is known; their route is cascade testing (see 4. What to Do with Results)
  3. If the proband has died, testing can still proceed where a stored sample exists: a structurally normal heart at post-mortem calls for molecular autopsy (R138 below), whereas a cardiomyopathy at post-mortem is tested on the matching condition panel (R131–R133), where a genetic diagnosis would help the surviving relatives (ESC Class I; AHA Class 1)[2][6]

UK National Genomic Test Directory (Version 9, 2026/27[1])

General Requirements for All Tests

All testing should be:

  • Performed in parallel with expert phenotypic assessment in an Inherited Cardiac Clinic (ICC)
  • With clinical genetics support
  • Targeted at those where genetic/genomic diagnosis will guide management for proband or family

Full guidelines: National Genomic Test Directory (v9, 2026/27)

Arrhythmia

R127 Long QT Syndrome

▼

Testing Method: Small Panel (76 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE OR MORE):

  • QTc ≥500ms in repeated 12-lead ECGs
  • LQTS risk score ≥3.5 (Schwartz 2011)
  • QTc ≥480ms in repeated ECGs AND unexplained syncope
  • QTc ≥480ms AND sudden unexplained death <60 years in 1st/2nd degree relative

Main Genes (LQTS Panel)

KCNQ1 KCNH2 SCN5A CALM1 CALM2 CALM3 CACNA1C KCNE1 KCNE2 + 67 others

Secondary causes must be excluded before testing

R128 Brugada Syndrome

▼

Testing Method: Small Panel (13 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE):

  • Spontaneous Type 1 ST elevation ≥2mm in ≥1 right precordial lead
  • Type 1 ST elevation with Na-channel blocker, AND ONE OR MORE of: VF/VT, syncope, FH of SCD <45y, coved ECG in family, agonal respiration, atrial arrhythmias <30y
  • Sodium channel disease suspicion (atrial arrhythmias, sinus/conduction disease, QT prolongation)

Genes Tested

SCN5A GPD1L CACNA1C CACNB2 SCN1B + 8 others

R129 Catecholaminergic Polymorphic VT

▼

Testing Method: Small Panel (214 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Structurally normal heart, normal ECG, AND:

  • Exercise/catecholamine-induced bidirectional VT or polymorphic PVCs/VT/VF in patient <40 years, OR
  • Exercise-induced arrhythmias with positive FH of CPVT (symptomatic family member unavailable), OR
  • Same as above but age >40 years

Main Genes

RYR2 CASQ2 CALM1-3 TRDN TECRL + 209 others

R130 Short QT Syndrome

▼

Testing Method: Small Panel (224 genes) | Requesting Specialties: Cardiology, Clinical Genetics

  • QTc ≤330ms, OR
  • QTc <360ms AND (FH of SQTS OR FH of SCD ≤40y OR VT/VF survival)

Main Genes

KCNH2 KCNQ1 KCNJ2 + 221 others

Cardiomyopathy

R131 Hypertrophic Cardiomyopathy

▼

Testing Method: WES or Medium Panel | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE OR MORE):

  • Adult with wall thickness ≥15 mm in ≥1 LV segment, NOT explained solely by loading conditions (e.g. hypertension), AND age of onset <60 years
  • Child <18 years with LV wall thickness >2 standard deviations above predicted mean (z-score >2)
  • Increased LV wall thickness ≥13 mm in ≥1 LV segment, in patient with 1st degree relative with unequivocal disease (LVH ≥15 mm), where affected family member unavailable for testing
  • Deceased individual with pathologically confirmed HCM (post-mortem DNA analysis)

Genes Tested (Hypertrophic Cardiomyopathy Panel - 49 genes)

MYBPC3 MYH7 TNNT2 TNNI3 TPM1 ACTC1 MYL2 MYL3 + 41 others

Note: R135 Paediatric/syndromic cardiomyopathy should be used where atypical features suggest broader gene testing needed

R132 Dilated and Arrhythmogenic Cardiomyopathy

▼

Testing Method: WES or Medium Panel | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE OR MORE):

  • LVEDD >2 SD AND/OR reduced EF <45% (age/sex adjusted), AND age of onset <65 years
  • Criterion 2 (DCM with conduction): DCM with conduction defects, age of onset <65 years
  • Left and/or biventricular cardiomyopathy with variable myocardial dysfunction/fibrosis PLUS ventricular arrhythmias, after excluding inflammatory causes
  • Deceased individual with pathologically confirmed DCM/ACM, age of onset <65 years
  • Patient with DCM/ACM at ANY age if 1st degree relative has confirmed DCM/ACM

Main Genes Tested (DCM/ACM Panel)

TTN LMNA MYH7 BAG3 FLNC RBM20 SCN5A DSP PLN DES + others

Exclusions: DCM secondary to coronary disease or pressure/volume overload. Consult expert before testing DCM due to myocarditis, alcohol, peripartum, chemotherapy.

R133 Arrhythmogenic Cardiomyopathy (ACM/ARVC)

▼

Testing Method: Small Panel (134 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE OR MORE):

  • DEFINITE diagnosis by Modified Task Force Criteria (Marcus 2010[3]), age of onset <50 years
  • Deceased with pathologically confirmed ARVC, relatives will benefit from cascade testing
  • Identification of P/LP variant would complete diagnostic Task Force Criteria

Desmosomal Genes

PKP2 DSG2 DSC2 DSP JUP TMEM43 PLN FLNC + 126 others

Other

R138 Molecular Autopsy / Idiopathic VF

▼

Testing Method: WES/Medium Panel (841 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Post-mortem testing:

  • Sudden death with normal PM <40 years, OR
  • Sudden death with normal PM <60y with FH unexplained SCD <40y in 1st/2nd degree relative, OR
  • Sudden death with normal PM <60y with FH unexplained SCD <60y (relative also had normal PM)

Cardiac arrest survivors (idiopathic VF):

  • No phenotype on comprehensive evaluation (coronary, imaging, ECG provocation) AND age <45 years

Panel: 841 genes covering all ICC, channelopathies, cardiomyopathies, SCD-associated genes

These criteria are from the NHS England National Genomic Test Directory.[1]

Genetic Counselling

Pre-test information, informed consent and access to genetic counselling should be offered before testing and when the result returns[1][2], by a genetic counsellor or a clinician trained in genetics[3], whatever the result: P/LP, negative, or a VUS (classified on the ACMG/AMP 5-tier system)[4].

When to refer for genetic counselling
  • Confirmed diagnosis of inherited cardiac condition
  • Family history of inherited cardiac condition or sudden cardiac death
  • Family cascade screening
  • Reproductive planning in affected individuals

References & Review Date

Last reviewed: September 2026

Gene panels & eligibility

  1. NHS England. National Genomic Test Directory (2026/27, v9). April 2026. Available at: england.nhs.uk/publication/national-genomic-test-directories/
  2. Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194
  3. Marcus FI, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Circulation. 2010;121(13):1533–1541. DOI: 10.1161/CIRCULATIONAHA.108.840827
  4. Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. DOI: 10.1093/eurheartj/ehac262
  5. Musunuru K, et al. Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association. Circ Genom Precis Med. 2020;13(4):e000067. DOI: 10.1161/HCG.0000000000000067
  6. Ommen SR, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Circulation. 2024;149(23):e1239–e1311. DOI: 10.1161/CIR.0000000000001250

Genetic counselling

  1. Charron P, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715–2728. DOI: 10.1093/eurheartj/ehq271
  2. Musunuru K, et al. Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association. Circ Genom Precis Med. 2020;13(4):e000067. DOI: 10.1161/HCG.0000000000000067
  3. Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194
  4. Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. DOI: 10.1038/gim.2015.30
  5. Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. DOI: 10.1093/eurheartj/ehac262

Tiered testing strategy

ICC genetic investigation follows a tiered approach, under the guidance of the cardiac genetics team, escalating to broader and more expensive tests only when simpler methods are insufficient.

1
First-Line = Targeted Next-Generation Sequencing (NGS) Gene Panel
  • Pathogenic / Likely Pathogenic: testing complete (see 4. What to Do with Results)
  • Variant of Uncertain Significance (VUS): not a diagnosis; segregation studies before any decision
  • Negative: escalate to Tier 2 if clinical suspicion remains high
↓ panel negative or inconclusive with ongoing clinical suspicion
2
Second-Line = Whole Exome Sequencing (WES)
What it adds: Broadens the search to all protein-coding genes. Consider trio WES (sequencing the proband plus both biological parents) as an alternative to solo WES when any of the following apply:
  • Paediatric or severe early-onset phenotype
  • Suspected de novo variant (no family history, normal parental phenotypes)
  • Syndromic features or intellectual disability
  • Consanguineous family (biallelic variants suspected)
NB: WES does not reliably detect large deletions or duplications; chromosomal microarray (CMA) can also be considered, as a separate test, if syndromic features suggest a microdeletion syndrome.
↓ WES negative or non-coding / structural variant strongly suspected
3
Third-Line = Whole Genome Sequencing (WGS)
What it adds: Includes non-coding regions, structural variants, and repeat expansions. Primarily via national genomics programmes (e.g. NHS Genomic Medicine Service).
  • Add trio design if a de novo variant is still suspected in a paediatric or unresolved case
  • Consider RNA sequencing (RNA-seq) alongside if a splice-disrupting variant is suspected but unconfirmed by DNA analysis
↓ pathogenic or likely pathogenic result identified at any tier
→
Post-Result Pathways
  • Cascade testing: offer targeted single-variant testing to first-degree relatives via cardiac genetics
  • Genetic counselling: discuss family planning, employment, and insurance implications with a multidisciplinary team (MDT)
  • Reproductive options: preimplantation genetic testing (PGT-M) via in vitro fertilisation (IVF), or invasive prenatal testing (chorionic villus sampling, CVS, or amniocentesis)
  • VUS ongoing review: segregation studies, functional evidence, periodic database reanalysis

Interpreting a genetic test result

ResultMeaningWhat to do
Pathogenic / Likely Pathogenic (P/LP)A disease-causing variant that fits the phenotypeUse for cascade testing; counsel relatives
Variant of Uncertain Significance (VUS)Insufficient evidence to classify either wayDo not use for predictive testing; see note below
NegativeNo reportable variant foundDoes not exclude inherited disease; continue phenotype-based family screening where indicated
Carrier / heterozygous (AR condition)Usually not sufficient alone to cause an autosomal recessive diseaseInterpret in the context of the specific condition and any second variant
Secondary / incidental findingAn actionable finding unrelated to the reason for testingManage via the clinical genetics pathway, separately from the primary indication

A VUS is not a positive result. It should not be used to reassure or discharge relatives, and should not be used for predictive cascade testing.[3] It may be reclassified in either direction as evidence accumulates: segregation within the family, phenotype refinement, functional studies, population frequency (gnomAD), computational predictors (SIFT, PolyPhen, SpliceAI), or laboratory reanalysis.

Serial re-evaluation of any identified variant is a Class 1 recommendation[6][5]: tell patients at consent that the interpretation may change and they may be recontacted, and note that a reclassification can reopen a family that was previously discharged.

What a negative result means, by scenario

ScenarioWhat the negative result means
Strong familial HCM phenotype, negative panelA genetic cause may still be present but undetected, or reflect a polygenic background (HCM is ~40–60% genotype-negative)
Brugada phenotype, negative SCN5ACommon and expected: SCN5A only accounts for ~20–30% of Brugada syndrome; a negative result does not exclude the diagnosis
Definite Fabry phenotype, negative GLAUnusual, since Fabry is close to 100% monogenic; recheck the phenotype, enzyme assay and testing quality rather than accepting the negative at face value
DCM with a strong acquired trigger (myocarditis, alcohol, tachycardia)Genetic yield is lower in this context; interpret alongside the acquired cause, and seek expert interpretation before excluding a genetic contribution entirely

Family screening & cascade testing

Cascade testing is the single most cost-effective use of a genetic result: once a P/LP variant is confirmed in an affected proband, relatives can be offered a fast, cheap, targeted single-variant test rather than a broad panel.[1][2]

1
Proband tested
Condition-matched panel, WES, or WGS as clinically indicated (see 3. How to Test).
→
2
P/LP found: relatives offered targeted testing
Single-variant test, not a repeat panel.
→
3
Outcome
Genotype-positive: condition-specific surveillance.
Genotype-negative: discharged with a safety net (see Surveillance below).

What to test in relatives

Proband resultRelative testing
P/LP variantTargeted single-variant testing
VUS, testing affected relatives or parentsSegregation testing should be considered (Class IIa) where it might allow the variant to be interpreted with confidence[5]
VUS, testing phenotype-negative relativesNot for predictive purposes. Usefulness purely for variant reclassification is uncertain (AHA Class 2b)[6]
NegativeClinical (phenotype-based) screening, not genetic predictive testing
No proband available for testingConsider testing another affected relative, or molecular autopsy if the proband is deceased (see Who to Test, R138)
Children in a family with a known P/LP variantCascade testing should be considered (Class IIa), weighed against four factors: the underlying cardiomyopathy, the expected age of onset, how the disease has presented in this family, and the clinical and legal consequences of testing a child[5]
A first-degree relative who has diedDo not let the branch stop there. Clinical evaluation of that person's own close relatives, i.e. second-degree relatives of the index patient, should be considered (Class IIa)[5]

Surveillance after the result

ESC 2023 and AHA 2024 give slightly different surveillance intervals; either is reasonable to follow.

WhoESC 2023AHA 2024 (HCM)
Genotype-positive, phenotype-negative ECG and echocardiography from childhood to old age: every 1 to 3 years up to age 60, then every 3 to 5 years[5] Every 1 to 2 years in children and adolescents, every 3 to 5 years in adults[6]
Relatives where no P/LP variant was found in the proband, or no genetic testing was done An initial multiparametric evaluation with ECG and cardiac imaging is recommended (Class I); regular long-term evaluation should be considered (Class IIa)[5] Clinical screening of first-degree relatives with ECG and echocardiography is offered alongside cascade testing (Class 1)[6]
Genotype-negative relatives in a genotype-positive family Discharged, with advice to return if symptoms develop or new family information emerges (Class I)[5] Ongoing screening is not indicated (Class 3: No Benefit), unless the familial variant is later downgraded to a VUS, likely benign or benign[6]

Reproductive options & variant follow-up

Reproductive options
Preimplantation Genetic Testing (PGT-M)
IVF-based embryo selection before implantation
Unaffected embryos selected at blastocyst stage before IVF transfer. Avoids transmission without requiring termination. Requires full IVF cycle. Regulated by HFEA in UK; eligibility requires high penetrance and significant morbidity/mortality.
Example: Couple with KCNQ1 LQT1 pathogenic variant → PGT-M selects unaffected embryos; unaffected pregnancy achieved.
Prenatal Genetic Testing
CVS or amniocentesis for a known family variant
CVS: ≥10 weeks; miscarriage risk ~0.5–1%. Amniocentesis: ≥15 weeks; miscarriage risk ~0.1–0.5%. Most relevant for severe early-onset conditions (Pompe, Danon, neonatal LQTS). Counselling must be non-directive.
Example: Known RYR2 pathogenic variant → amniocentesis confirms fetal genotype; if positive, neonatal surveillance and early beta-blocker planned pre-delivery.
Variant interpretation & follow-up
VUS Management
Variant of Uncertain Significance, principles
Do not use a VUS alone to drive ICD implantation, sport restriction, or cascade testing (evidence sources: see the VUS note under Interpreting a genetic test result).
Example: MYH7 missense VUS → found in 3/4 affected relatives, absent from 2 unaffected → reclassified likely pathogenic (PP1 + PS3 criteria met).
Genetic Reanalysis
Revisiting stored data as knowledge evolves
Periodic reanalysis of stored WES/WGS data against updated databases (ClinVar, gnomAD) and expanded gene lists. Diagnostic yield ~10–15% of previously unsolved cases. Driven by new gene–disease associations (ALPK3, FLNC) and VUS reclassifications.
Example: FLNC VUS in 2019 → reclassified likely pathogenic in 2023 reanalysis (new NDLVC evidence) → diagnosis without re-sequencing.

References & Review Date

Last reviewed: September 2026

  1. Musunuru K, et al. Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association. Circ Genom Precis Med. 2020;13(4):e000067. DOI: 10.1161/HCG.0000000000000067
  2. Charron P, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715–2728. DOI: 10.1093/eurheartj/ehq271
  3. Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. DOI: 10.1038/gim.2015.30
  4. Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. DOI: 10.1093/eurheartj/ehac262
  5. Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194
  6. Ommen SR, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Circulation. 2024;149(23):e1239–e1311. DOI: 10.1161/CIR.0000000000001250

Assay & analysis methods

DNA analysis · by scale of change
Sequencing-based assayssingle bases to whole genome

Detect single nucleotide variants (SNVs) and small insertions/deletions across a range of genomic scope, from condition-specific gene panels to whole genome. Trio testing (proband + both parents sequenced simultaneously) falls within this category.

When to order: The starting point for almost every ICC genetic test: when a clinical diagnosis or a known family variant makes a sequence-level cause (a single-base change or small indel) likely.

Assay When to Order What It Detects Technical Approach Key Limitations ICC Application
Targeted Gene Panel (NGS)
  • First-line in clinically suspected ICC
  • Proband with HCM, DCM, ARVC, LQTS, CPVT, Brugada
  • Not for cascade testing (see Sanger, below)
 SNVs and small indels in a curated set of disease-associated genes (typically 50–300 genes) NGS of enriched target regions; bioinformatic variant calling against reference genome
  • Misses variants outside the gene panel
  • Generally cannot detect large CNVs
  • Non-coding variants missed
 HCM panel (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, ACTC1); LQTS panel (KCNQ1, KCNH2, SCN5A); ARVC panel (PKP2, DSP, DSC2, DSG2, JUP)
Sanger Sequencing
  • Confirming a variant identified on NGS panel
  • Cascade testing when family variant is already known (single-site)
 Point mutations and small indels in a single amplicon (~200–1000 bp) Dideoxy chain termination; fluorescent capillary electrophoresis of a single PCR product
  • Very low throughput, one amplicon per run
  • Cannot detect CNVs
  • Not suitable for novel discovery
 Confirming MYH7 p.Arg403Gln in at-risk relatives of a known HCM family; validating a KCNH2 variant before cascade testing
Whole Exome Sequencing (WES)
  • Panel-negative with strong clinical suspicion
  • Atypical or syndromic phenotype
  • Rare or undiagnosed cardiomyopathy
  • Paediatric cases where diagnosis is uncertain
 SNVs and indels across all ~20,000 protein-coding exons (~1–2% of genome) Hybridisation capture enriches exome; NGS library sequenced to ~100× depth; phenotype-driven gene prioritisation
  • Misses non-coding regions (introns, promoters)
  • Limited CNV detection
  • Repeat expansions not reliably called
  • Higher VUS burden than targeted panels
 Novel truncating RBM20 variant in panel-negative familial DCM; FLNC truncating variant in NDLVC after negative panel
Trio Exome Sequencing
Proband + both parents
  • Severe early-onset or paediatric phenotype
  • Suspected de novo variant
  • Syndromic features of unknown cause
  • Consanguineous family (biallelic variants suspected)
  • Solo WES inconclusive
 De novo variants; compound heterozygous variants with phasing; inherited variants with one-step segregation data As WES; de novo calling compares the child\'s variants against both parents\'; increases diagnostic yield vs solo WES
  • Requires both biological parents to provide samples
  • Higher cost than solo WES
  • Still misses non-coding variants and repeat expansions
 De novo KCNQ1 in neonatal LQTS; de novo PTPN11 in a Noonan-associated HCM phenotype; compound heterozygous MYH7/MYBPC3 in severe paediatric HCM
Whole Genome Sequencing (WGS)
  • Unresolved after panel + WES
  • Suspected non-coding, intronic, or structural variant
  • Repeat expansion disorder (Friedreich, myotonic dystrophy)
  • Research or national genomics programme
  • Trio design (both parents) when a de novo non-coding or structural variant is suspected
 SNVs, indels, CNVs, structural variants, non-coding variants, and repeat expansions across the entire genome NGS without prior target enrichment; ~30–50× depth; dedicated structural-variant and repeat-expansion calling
  • High cost and large data volumes
  • Very high VUS burden in non-coding regions
  • Non-coding variant interpretation remains limited clinically
 Non-coding LMNA promoter variant in familial DCM; FXN GAA repeat expansion in a Friedreich-associated HCM phenotype; DMPK CTG expansion in myotonic dystrophy cardiomyopathy
Copy number & structural analysisexon to gene level

Detect exon-level or gene-level deletions and duplications. Used as an adjunct when standard sequencing is negative but a copy number change is suspected based on clinical features or incomplete co-segregation.

When to order: When sequencing is negative or inconclusive but the phenotype or family co-segregation still points to a disrupted gene, so a deletion or duplication too large for sequencing to call is the likely explanation.

Assay When to Order What It Detects Technical Approach Key Limitations ICC Application
MLPA
Multiplex Ligation-dependent Probe Amplification
  • Suspected exon-level CNV after negative sequencing
  • Known family CNV
 Exon-level deletions and duplications in targeted genes (typically 40–50 probes covering one or a few genes) Probe pairs flanking each exon ligated and PCR-amplified; capillary electrophoresis quantifies relative probe copy number
  • Only detects CNVs within pre-designed probe regions
  • Cannot detect point mutations or balanced rearrangements
  • Requires a gene-specific probe kit
 PKP2 exon 1–5 deletion in sequence-negative ARVC; LDLR CNV (~15% of pathogenic FH variants); LMNA exon deletion in conduction-system DCM
qPCR / ddPCR
Quantitative / Digital Droplet PCR
  • Targeted CNV confirmation after CMA or MLPA
  • Known family variant follow-up where MLPA unavailable
 Relative copy number of specific targeted loci; gene expression levels via RT-qPCR Fluorescent probe quantification relative to reference gene; ddPCR partitions reaction into droplets for absolute digital counting
  • Only analyses pre-defined target regions
  • Requires prior knowledge of variant
  • Not suitable for discovery
 LMNA exon deletion quantification in familial DCM before cascade testing; DMD exon copy number confirmation in Duchenne cardiomyopathy
Cytogenetic analysischromosome level

Detect chromosomal-scale abnormalities, from whole-chromosome aneuploidies (karyotyping) to sub-megabase copy number changes (microarray). Indicated for syndromic presentations or congenital heart disease.

When to order: When the cardiac phenotype is part of a wider syndrome (dysmorphic features, developmental delay, congenital heart disease) or a chromosomal cause is suspected, including in pregnancy.

Assay When to Order What It Detects Technical Approach Key Limitations ICC Application
Chromosomal Microarray (CMA)
  • Syndromic ICC with dysmorphic features, intellectual disability, or congenital heart disease
  • Suspected microdeletion/duplication syndrome (22q11, Williams, Noonan region)
  • Panel and WES negative with syndromic features persisting
 CNVs (microdeletions and microduplications) at ≥50 kb resolution genome-wide; regions of homozygosity (ROH) SNP or CGH array; patient DNA hybridised against reference; signal intensity ratios indicate copy number; SNP arrays also reveal regions of homozygosity
  • Cannot detect balanced translocations or point mutations
  • UPD without LOH not detected
  • CNVs below ~50 kb missed
 22q11.2 deletion (DiGeorge) + DCM + congenital heart defect; 7q11.23 deletion (Williams) + supravalvular aortic stenosis; NF1 microdeletion in a Noonan-related HCM phenotype
Karyotyping
G-banded chromosome analysis
  • Suspected aneuploidy with cardiomyopathy (Down, Turner, Klinefelter)
  • Congenital heart disease + dysmorphic features
  • Suspected balanced translocation disrupting a cardiac gene
 Whole-chromosome abnormalities: aneuploidies, large structural rearrangements, balanced and unbalanced translocations (>5–10 Mb resolution) Blood lymphocytes cultured and arrested in metaphase; G-banding stain; microscopic karyogram of 22 autosomes + sex chromosomes
  • Poor resolution (~5–10 Mb); misses microdeletions detectable by CMA
  • Largely superseded by CMA for most syndromic indications
 Turner syndrome (45,X) + bicuspid aortic valve; trisomy 21 + AVSD + dilated cardiomyopathy; balanced t(1;3) disrupting FLNC in unexplained RCM
FISH
Fluorescence In Situ Hybridisation
  • Confirming a specific known deletion (e.g. 22q11.2) after clinical suspicion or CMA screen
  • Rapid aneuploidy detection in prenatal samples
 Specific chromosomal deletions, amplifications, or translocations at a single targeted locus Fluorescent probes hybridise to denatured chromosomal DNA; fluorescence microscopy detects copy number at the specific locus
  • Requires prior knowledge of region, cannot discover novel abnormalities
  • Single-locus; replaced by CMA for genome-wide analysis
 22q11.2 deletion confirmation in DiGeorge syndrome + DCM; rapid trisomy 21 detection in fetal cardiac sample
Non-Invasive Prenatal Testing (NIPT)
  • Prenatal screening in families at risk of a chromosomal syndrome with cardiac involvement
 Fetal aneuploidies (trisomy 21, 18, 13; sex chromosome abnormalities) from cell-free fetal DNA (cffDNA) in maternal blood; selected microdeletion syndromes on extended panels Cell-free DNA from maternal plasma (~10–15% fetal fraction); massively parallel sequencing; statistical over/under-representation of chromosomal regions infers fetal copy number
  • Screening only, positive requires confirmatory CVS or amniocentesis
  • Cannot diagnose monogenic ICC family variants
  • False positives on microdeletion panels
 Trisomy 21 screening in fetus at risk of AVSD; 22q11.2 screening in family with DiGeorge syndrome
RNA analysis
Transcriptomic analysisRNA & splicing

Analyses RNA rather than DNA. Used to confirm whether a DNA variant disrupts normal splicing or gene expression, primarily in specialist or research settings. Requires tissue in which the gene of interest is actively expressed.

When to order: When a DNA result is unresolved (a variant of uncertain significance predicted to affect splicing, or a phenotype the DNA findings do not explain) and the gene is expressed in a tissue that can be sampled; specialist or research settings.

Assay When to Order What It Detects Technical Approach Key Limitations ICC Application
RNA Sequencing (RNA-seq)
  • VUS with predicted splicing effect
  • Deep intronic or cryptic splice-site variant
  • Discordance between phenotype and genetic findings
  • Research investigation of cardiac gene expression
 Aberrant splicing, exon skipping, cryptic exon use, allele-specific expression, fusion transcripts, and RNA expression levels RNA isolated from relevant tissue; reverse-transcribed to cDNA; NGS library sequenced; splice junctions and expression compared to reference transcriptome
  • Gene must be expressed in available tissue, many cardiac genes not expressed in blood
  • Requires fresh/frozen tissue; FFPE unsuitable
  • Not routine clinical practice; primarily research
 TTN deep intronic variant causing exon skipping in DCM (cardiac biopsy RNA); PKP2 aberrant splice isoform in ARVC; SCN5A splice variant reclassification in Brugada syndrome

Genetics Glossary

A single reference glossary of commonly used molecular genetics, inheritance, and laboratory terms.

Variant & Mutation Types
Copy Number Variant (CNV)Large-scale deletion or duplication
Structural genomic variants involving deletion or duplication of segments typically >1 kb, affecting one or more exons or entire genes. CNVs account for ~15% of pathogenic LDLR variants in FH and are not reliably detected by standard Sanger sequencing, MLPA or whole-genome sequencing is required.
Example: LDLR exon 1–6 deletion → complete loss of LDL receptor in affected exons → severe FH phenotype.
Frameshift VariantReading frame disrupted by indel
Insertion or deletion of a number of nucleotides not divisible by three, shifting the reading frame so that every downstream codon is altered and a premature stop almost always follows (see Truncating variant). One of the commonest truncating variant types in ICC genes.
Example: MYBPC3 c.2373insG, a single-base insertion → frameshift → premature stop → HCM.
Missense Variant (SNP)Single amino acid substitution
A single nucleotide change alters one codon, substituting a different amino acid. The resultant protein is full-length but structurally or functionally abnormal. Pathogenicity depends on the amino acid position and physicochemical change introduced.
Example: MYH7 p.Arg403Gln, glutamine substitution at the myosin motor domain disrupts cross-bridge cycling in HCM.
Nonsense Variant (Stop-Gain)Single nucleotide change creates stop codon
A single nucleotide substitution that converts a coding codon into a premature stop codon (UAA, UAG or UGA); see Truncating variant for the consequences.
Example: PKP2 p.Arg79*, an early stop codon → loss of plakophilin-2 → ARVC.
Repeat ExpansionPathological tandem repeat enlargement
Abnormal expansion of a repetitive DNA sequence beyond a pathological threshold. Underlies Friedreich's ataxia (FXN GAA repeat → hypertrophic cardiomyopathy phenotype with neuropathy) and myotonic dystrophy (DMPK CTG repeat → conduction disease and cardiomyopathy).
Example: FXN intron 1 GAA expansion >66 repeats → frataxin deficiency → HCM phenotype + progressive ataxia.
Splice-site VariantDisruption of exon–intron boundary signals
Variants at the canonical splice donor (GT) or acceptor (AG) dinucleotides, or within nearby intronic/exonic splicing regulatory sequences. Consequences range from exon skipping, intron retention, or activation of a cryptic splice site, all producing an aberrant mRNA. Most canonical splice-site variants result in a truncated protein and NMD, but exon-skipping variants may produce in-frame products with partial function.
Example: TTN splice-site variants in A-band exons with high PSI are among the most prevalent DCM variants; exon skipping produces non-functional titin isoforms.
Truncating VariantFrameshift, nonsense, or essential splice-site
Any variant that introduces a premature termination codon: a frameshift indel, a nonsense substitution, or disruption of an essential splice site. The usual outcome is nonsense-mediated decay (NMD) of the transcript, leaving only the wild-type allele's output (haploinsufficiency); a truncated protein that escapes NMD may instead act in a dominant-negative way.
Example: MYBPC3 frameshift → NMD → ~50% reduction in cMyBP-C → haploinsufficiency → HCM.
Molecular Mechanisms
Altered RNA SplicingDysregulation of transcript isoform production
Some pathogenic variants do not change the protein sequence directly but instead disrupt the normal regulation of pre-mRNA splicing, altering which exons are included in the final transcript. This produces abnormal isoform ratios with downstream functional consequences. A distinct category from splice-site variants, the causal variant may be in the coding region yet its effect is entirely on splicing.
Example: RBM20 RSRSP-domain missense variants prevent correct titin mRNA splicing → giant, non-compliant titin isoforms → impaired sarcomere mechanics in DCM.
Dominant Negative EffectMutant protein sabotages wild-type function
The abnormal protein actively interferes with the function of the normal wild-type protein produced from the remaining allele. Mechanistically more damaging than haploinsufficiency because total functional protein falls below 50%. Common in proteins forming multi-subunit complexes, the mutant subunit "poisons" the assembly.
Example: MYH7 missense variants incorporate into myosin thick filaments as "poison peptides", impairing cross-bridge cycling disproportionately.
Gain of Function (GoF)Novel or enhanced pathological activity
The variant confers a new or amplified activity not present in the wild-type protein. In ion channel diseases, GoF commonly means the channel fails to fully inactivate, generating persistent current that prolongs the action potential or causes abnormal spontaneous depolarisations.
Example: SCN5A GoF → persistent late INa → prolonged QT → LQT3; RYR2 GoF → abnormal SR Ca²⁺ release at rest → triggered VT in CPVT.
HaploinsufficiencyOne functional copy is insufficient
Disease that results when a single functional copy of a gene cannot produce enough protein for normal cellular function. Typical of dosage-sensitive structural proteins.
Example: MYBPC3, TTN, PKP2, DSP and LMNA all cause disease primarily through haploinsufficiency.
Increased Ca²⁺ SensitivityThin filament hyperactivation at rest
A mechanism specific to thin-filament HCM variants (TNNT2, TNNI3, TPM1). Troponin normally holds the thin filament inactive in diastole; these variants shift it towards the active state at low Ca²⁺, so the sarcomere never fully relaxes: incomplete relaxation, energy wastage and diastolic dysfunction, even with little or no hypertrophy.
Example: TNNT2 variants carry disproportionate SCD risk at near-normal wall thickness, because hyperactive sarcomeres consume ATP excessively.
Loss of Function (LoF)Reduced or absent normal protein activity
Any variant that reduces or abolishes the normal activity of a protein, whether by reduced expression, misfolding, defective trafficking or disruption of a binding site. Includes both truncating and missense variants.
Example: KCNQ1 LoF reduces IKs (slow delayed rectifier) current → prolonged action potential → LQT1.
Nonsense-Mediated Decay (NMD)mRNA quality-control surveillance
The cellular pathway that degrades mRNA carrying a premature termination codon located >50–55 nucleotides upstream of the last exon–exon junction. Stops in the last exon or near the C-terminus escape NMD, and the truncated protein may accumulate with dominant-negative effects.
Relevant to: MYBPC3, TTN, PKP2, DSP, where NMD of the mutant transcript is the main route to haploinsufficiency.
Protein Trafficking DefectFailure to reach the cell membrane
Missense variants may produce a structurally near-normal protein that is incorrectly folded and retained in the endoplasmic reticulum (ER) rather than being trafficked to the cell surface. The protein is then degraded, reducing functional surface expression. This is a major mechanism of LoF for KCNH2 variants in LQT2.
Example: Many KCNH2 missense variants in LQT2 cause ER retention of the hERG channel, functional consequence is LoF despite a structurally near-complete protein.
Triggered Activity (DADs)Spontaneous depolarisations from Ca²⁺ overload
Delayed afterdepolarisations (DADs) are spontaneous depolarisations in phase 4 of the action potential, driven by Ca²⁺ leaking from the sarcoplasmic reticulum. A DAD that reaches threshold fires a triggered beat: the cellular mechanism of ventricular arrhythmia in CPVT and PLN cardiomyopathy.
Example: RYR2 GoF → SR Ca²⁺ sparks under adrenergic stimulation → DADs → bidirectional VT, the signature arrhythmia of CPVT1.
Inheritance & Population Genetics
Allelic HeterogeneityDifferent variants cause different phenotypes
When different variants within the same gene produce distinct clinical phenotypes, different diseases, different severities, or even opposite functional mechanisms. Allelic heterogeneity is common in ICC genes and is clinically relevant because it means gene identification alone does not fully determine prognosis.
Example: SCN5A, GoF missense variants → LQT3; LoF variants → Brugada syndrome; severe LoF → DCM with conduction disease. Same gene, opposite mechanisms.
AnticipationEarlier onset or greater severity in successive generations
Seen with unstable repeat expansions that tend to lengthen each time they are transmitted, so the repeat size, and with it the age of onset and severity, worsens down the pedigree. A mildly affected or undiagnosed parent can therefore have a severely affected child, and a new diagnosis in a child should prompt assessment of the parent.
Example: Myotonic dystrophy type 1: the DMPK CTG repeat expands on transmission (most markedly through the mother), so a parent with cataracts and mild grip myotonia may have a child with the congenital form.
CarrierA word with two meanings; be explicit which one
Strictly, an unaffected heterozygote for an autosomal recessive condition. In the ICC literature "variant carrier" is also used loosely for anyone who has a pathogenic variant, including people with dominant or X-linked disease who are, or will become, affected. The loose sense misleads in X-linked conditions: a heterozygous female is not merely a carrier (see X-inactivation) and may develop significant disease. Prefer "heterozygous", "hemizygous" or "genotype-positive", and reserve "carrier" for the recessive sense.
Example: Fabry disease: a woman heterozygous for a pathogenic GLA variant is often labelled a carrier, yet a substantial proportion develop cardiac, renal or cerebrovascular disease and need surveillance in their own right.
Compound HeterozygosityTwo different variants in the same gene
In autosomal recessive disease, compound heterozygosity describes carrying two distinct pathogenic variants in the same gene, one on each chromosome, rather than the same variant on both chromosomes (homozygosity). Each parent carries one variant and is typically unaffected. Together the two variants produce severely reduced or absent protein function.
Example: CASQ2 compound heterozygous variants cause CPVT2 with earlier onset than heterozygous carrier parents.
De Novo VariantNew mutation absent in both parents
A pathogenic variant arising for the first time in the proband, inherited from neither parent; found in ~4–5% of ICC cases, typically severe early-onset presentations without a family history. Parents and siblings are at very low risk (barring gonadal mosaicism), but offspring have a 50% transmission risk.
Example: Severe neonatal Marfan syndrome is often caused by a de novo FBN1 variant; unaffected parents do not exclude a genetic cause.
Digenic InheritanceVariants in two genes required for disease
A pattern where pathogenic variants in two distinct genes, each individually insufficient to cause severe disease, combine to produce a more severe phenotype or clinical disease. Seen particularly in ARVC, where compound heterozygosity across two desmosomal genes (e.g., PKP2 + DSG2) amplifies disease penetrance and severity beyond either variant alone.
Example: ARVC patients carrying variants in both PKP2 and DSP have significantly higher penetrance, earlier onset, and greater arrhythmia burden than carriers of a single desmosomal variant.
Founder VariantPopulation-enriched pathogenic allele
A pathogenic variant present at relatively high frequency in a specific population due to descent from a common ancestor who carried it (founder effect). Important for population-specific diagnostic panels, targeted assays for founder variants can provide efficient first-line screening before full gene sequencing.
Example: MYBPC3 c.2373insG (~4% of HCM in South Asians); PLN p.Arg14del (Dutch/N. European DCM); JUP c.2157del2 (Greek island ARVC).
Gonadal (Germline) MosaicismVariant confined to some of a parent's egg or sperm cells
A parent whose blood test is negative may still carry the variant in a proportion of their germ cells, so an apparently de novo variant can recur in a later child. Because of this, the recurrence risk after a de novo finding is quoted as low (about 1%) rather than zero, and prenatal or preimplantation testing is still offered for subsequent pregnancies.
Example: Two siblings with the same "de novo" FBN1 variant while both parents test negative on blood, the variant is present in one parent's germline only.
Hemizygous / Heterozygous / HomozygousHow many copies of a variant an individual has
Heterozygous: one copy of the variant with a normal allele on the other chromosome, the usual state in dominant ICCs. Homozygous: the same variant on both copies, the usual state in recessive disease and, in dominant ICC genes, generally a severe early-onset phenotype. Hemizygous: only one copy of the gene exists at all, so a single variant is fully expressed with no second allele to offset it, the situation for X-linked genes in males.
Example: GLA (Fabry): hemizygous males have classic disease; heterozygous females range from unaffected to severe. Homozygous or compound heterozygous MYBPC3 variants cause severe infantile HCM.
Obligate CarrierMust carry the familial variant by pedigree logic, tested or not
An individual whose position in the pedigree means they must have the familial variant, whether or not they have been tested or show disease: both parents of a child with autosomal recessive disease; every daughter of a male with an X-linked condition; the mother of an affected son who also has an affected brother or maternal uncle; and, in a dominant family, an unaffected person whose parent and child both carry the variant (non-penetrance). Confirmatory testing is still usually offered, and the label says nothing about clinical status: in X-linked disease an obligate heterozygote may be significantly affected and needs assessment in her own right.
Example: Every daughter of a man with Fabry disease is an obligate heterozygote for his GLA variant; a woman with an affected son and an affected brother is an obligate heterozygote for a DMD variant.
PenetranceProportion of carriers who develop disease
The probability that a variant carrier will manifest clinical disease. Complete penetrance means virtually all carriers are affected. Incomplete penetrance is common in ICCs, some pathogenic variant carriers remain phenotype-negative throughout life. Penetrance is age-dependent and modified by sex, physical activity, and modifier genes.
Example: MYBPC3 HCM variants have strongly age-related penetrance, many carriers are unaffected until the 4th–5th decade; TTN DCM variants have ~40% penetrance in males.
PhasingDetermining which parental chromosome a variant is on
Establishing whether a variant is on the maternally or paternally inherited copy of a gene. Critical when two variants are found in the same gene: in trans (one on each chromosome = biallelic = AR disease) versus in cis (both on same chromosome = monoallelic).
ProbandIndex case in a family
The first affected individual in a family to undergo genetic testing. Results from the proband guide which specific variant is used in subsequent cascade testing of relatives.
SegregationVariant co-occurrence with disease in a family
The pattern of a variant being present in affected family members and absent from unaffected ones. Each additional affected relative carrying the variant increases the LOD score, building evidence towards LP reclassification for a VUS.
Variable ExpressivitySame variant, different severity
Even when a pathogenic variant is penetrant, the severity and features of the phenotype vary considerably between carriers of the same variant, including within the same family. Modifier genes, lifestyle (e.g., exercise load), sex hormones, and epigenetic factors all contribute to expressivity.
Example: FBN1 Marfan variants, one family member may have severe aortic root aneurysm while another has only ectopia lentis with a normal aorta.
X-inactivation (Lyonisation)Random silencing of one X in female cells
Early in female embryogenesis each cell randomly silences one X chromosome, so about half of cells express each parental allele. If the pathogenic X is preferentially silenced (skewed inactivation) a female carrier may stay unaffected; if preferentially expressed, her phenotype can approach that of an affected male.
Example: Female LAMP2 (Danon) carriers range from phenotype-negative into middle age to significant cardiomyopathy, depending on which X predominates.
X-linked InheritanceGene located on the X chromosome
X-linked dominant (XLD): one pathogenic allele causes disease in both sexes, more severely in males, who lack a second X. X-linked recessive (XLR): females are usually unaffected carriers; hemizygous males are affected. Neither form shows male-to-male transmission. Female severity in XLD depends on X-inactivation.
Example: GLA (Fabry) and LAMP2 (Danon) → XLD; EMD (Emery-Dreifuss) → XLR, only males clinically affected.
Mitochondrial Genetics
HeteroplasmyMitochondrial variant allele fraction
The proportion of a cell's many mtDNA copies that carry a pathogenic variant. Disease appears only once heteroplasmy exceeds a tissue-specific threshold, lowest in high-energy tissues such as heart and skeletal muscle, which is why carriers of the same variant range from asymptomatic to severe multisystem disease. Levels differ between tissues (blood may underestimate cardiac load) and shift across generations.
Example: m.3243A>G at 10–30% may cause only diabetes or deafness; above ~60–70% in affected tissues it produces full MELAS with cardiomyopathy and stroke-like episodes.
HomoplasmyAll mitochondria carry the same mtDNA
When all copies of mtDNA within a cell or tissue carry the same sequence, either entirely wild-type (normal) or entirely the pathogenic variant. Homoplasmy for a pathogenic variant generally produces more severe, fully penetrant disease than heteroplasmy. Some mtDNA variants causing cardiomyopathy can be homoplasmic, as they may be relatively tolerated in tissues outside the heart and muscle.
Example: Certain MT-TL1 and MT-ATP6 variants associated with a hypertrophic cardiomyopathy phenotype are transmitted and expressed homoplasmatically, resulting in predictable and fully penetrant cardiac involvement.
Maternal InheritanceMitochondrial DNA is maternally transmitted
Mitochondrial DNA (mtDNA) is inherited exclusively through the maternal lineage, sperm mitochondria are degraded after fertilisation. All children of an affected mother are at risk of inheriting the variant; no children of an affected father are at risk. Pedigree analysis should identify strictly maternal transmission when a mitochondrial disorder is suspected.
Example: m.3243A>G is transmitted by affected mothers to all offspring; an affected father does not transmit, paternal transmission effectively rules out an mtDNA disorder.
Sequencing & Laboratory Concepts
Allele-Specific ExpressionImbalanced expression from one parental allele
When one allele of a gene is expressed at significantly lower levels than the other, due to a regulatory or splicing variant on that allele. Detectable by RNA-seq; can support pathogenicity reclassification of a VUS affecting transcription or splicing efficiency.
AneuploidyAbnormal chromosome number
Presence of an abnormal number of chromosomes. ICC-relevant examples: trisomy 21 / Down syndrome (AVSD, DCM), Turner syndrome 45,X (bicuspid aortic valve, aortic coarctation), Klinefelter 47,XXY (DCM).
Coverage / Sequencing DepthTimes each base is read
The average number of times each DNA base is sequenced. Higher depth (~100× for WES, ~30–50× for WGS) increases confidence in variant calls and reduces false negatives.
Cryptic ExonNormally silent intronic sequence included in mRNA
An intronic sequence aberrantly included in mature mRNA when a nearby variant activates a cryptic splice site (see Splice-site variant); usually frameshifting, and invisible to WES/WGS without RNA-seq.
CytogeneticsStudy of chromosomes and chromosome-scale changes
Analysis of chromosome number and large-scale structural organisation. Encompasses karyotyping (microscopy), FISH (fluorescent probe hybridisation), and chromosomal microarray (genome-wide copy number). Used for syndromic and congenital presentations.
Diagnostic YieldProportion receiving a genetic diagnosis
The proportion of tested individuals in whom a P/LP variant is identified. Varies by condition: ~60% HCM, ~30–40% DCM, ~50–60% LQTS, ~50% ARVC. Lower yields reflect incomplete knowledge of causative genes.
ExomeProtein-coding portion of the genome
The ~1–2% of the genome that encodes proteins, comprising ~20,000 genes. Whole exome sequencing (WES) captures and sequences this region to ~100× depth.
NGS (Next-Generation Sequencing)High-throughput DNA sequencing
Produces millions of short DNA reads simultaneously, enabling rapid sequencing of many genes at once. The technology underlying gene panels, WES, and WGS.
ROH (Regions of Homozygosity)Identical alleles on both chromosomes
Stretches of identical alleles on both chromosome copies, detected by SNP microarray. Extensive ROH indicates consanguinity; isolated ROH can indicate uniparental disomy (UPD), relevant for imprinting disorders affecting the heart.
TranscriptomeComplete RNA output of a cell
The full set of RNA molecules expressed by a cell or tissue. Tissue-specific, cardiac genes (TTN, PKP2, SCN5A) may not be expressed in blood, limiting RNA-seq utility to biopsy samples in ICC.
VCF (Variant Call Format)Bioinformatic output file
Standard file listing all differences between a patient's DNA and the reference genome after sequencing analysis. Clinical filtering narrows hundreds of thousands of raw variants to a small number of candidates.
Variant Classification (ACMG)
ACMG ClassificationFive-tier variant classification framework
Standard framework used by clinical laboratories: Pathogenic (P), Likely Pathogenic (LP), VUS, Likely Benign (LB), Benign (B). Based on population frequency, functional data, segregation, and computational evidence criteria.
VUS (Variant of Uncertain Significance)Inconclusive genetic finding
A variant with insufficient evidence to classify as pathogenic or benign. Common with WES/WGS. Should not alone drive major clinical decisions; requires ongoing evidence accumulation and review.

Last reviewed: September 2026

Gene Variants

Gene Variants in Inherited Cardiac Conditions

Genes with established evidence for inherited cardiac conditions, grouped by the phenotype they cause.

Gene Condition Affected Component Inheritance Mutation Type Molecular Effect Genotype–Phenotype Relationships

A gene that causes several phenotypes appears under each; within a row genes are ordered by prevalence, and the major gene(s) for that phenotype are in bold.

The corner figure is the headline frequency where one is expressed as a percentage.

Genotypes tabulated as high-risk in the 2023 ESC cardiomyopathy guideline are flagged.[9]

The list is not exhaustive: gene–disease validity is reappraised as evidence accumulates and genes move between tiers.[23][24][25][26]

Prevalence, penetrance and mechanism figures derive largely from referral cohorts and are indicative rather than fixed.[1][2]

How common each condition is in the population: prevalence graphic.

References & Review Date

Last reviewed: September 2026

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  2. Richard P, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107(17):2227–2232. DOI: 10.1161/01.CIR.0000066323.15244.54
  3. Herman DS, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366(7):619–628. DOI: 10.1056/NEJMoa1110186
  4. Schwartz PJ, et al. Inherited cardiac arrhythmias. Nat Rev Dis Primers. 2020;6(1):58. DOI: 10.1038/s41572-020-0188-7
  5. Priori SG, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2015;36(41):2793–2867. DOI: 10.1093/eurheartj/ehv316
  6. Corrado D, et al. Diagnosis of arrhythmogenic cardiomyopathy: the Padua criteria. Int J Cardiol. 2020;319:106–114. DOI: 10.1016/j.ijcard.2020.06.005
  7. Nordestgaard BG, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population. Eur Heart J. 2013;34(45):3478–3490. DOI: 10.1093/eurheartj/eht273
  8. Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47(7):476–485. DOI: 10.1136/jmg.2009.072785
  9. Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194
  10. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10(9):531–547. DOI: 10.1038/nrcardio.2013.105
  11. van der Zwaag PA, et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail. 2012;14(11):1199–1207. DOI: 10.1093/eurjhf/hfs119
  12. Narasimhan B, et al. Brugada syndrome. Nat Rev Dis Primers. 2025;11(1):38. DOI: 10.1038/s41572-025-00622-5
  13. Priori SG, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103(2):196–200. DOI: 10.1161/01.CIR.103.2.196
  14. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. DOI: 10.1186/1750-1172-5-30
  15. Nishino I, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 2000;406(6798):906–910. DOI: 10.1038/35022604
  16. El-Hattab AW, et al. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. 2015;116(1–2):4–12. DOI: 10.1016/j.ymgme.2015.06.004
  17. Loeys BL, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37(3):275–281. DOI: 10.1038/ng1511
  18. Byers PH, et al. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. 2017;175(1):40–47. DOI: 10.1002/ajmg.c.31553
  19. Asatryan B, et al. Natural history, phenotype spectrum, and clinical outcomes of desmin (DES)-associated cardiomyopathy. Circ Genom Precis Med. 2025;18(2):e004878. DOI: 10.1161/CIRCGEN.124.004878
  20. Bermúdez-Jiménez FJ, et al. Phenotype and clinical outcomes in desmin-related arrhythmogenic cardiomyopathy. JACC Clin Electrophysiol. 2024;10(6):1178–1190. DOI: 10.1016/j.jacep.2024.02.031
  21. van Spaendonck-Zwarts KY, et al. Desmin-related myopathy. Clin Genet. 2011;80(4):354–366. DOI: 10.1111/j.1399-0004.2010.01512.x
  22. Brodehl A, Gaertner-Rommel A, Milting H. Molecular insights into cardiomyopathies associated with desmin (DES) mutations. Biophys Rev. 2018;10(4):983–1006. DOI: 10.1007/s12551-018-0429-0
  23. Ingles J, et al. Evaluating the clinical validity of hypertrophic cardiomyopathy genes. Circ Genom Precis Med. 2019;12(2):e002460. DOI: 10.1161/CIRCGEN.119.002460
  24. Jordan E, et al. Evidence-based assessment of genes in dilated cardiomyopathy. Circulation. 2021;144(1):7–19. DOI: 10.1161/CIRCULATIONAHA.120.053033
  25. James CA, et al. International evidence based reappraisal of genes associated with arrhythmogenic right ventricular cardiomyopathy using the Clinical Genome Resource framework. Circ Genom Precis Med. 2021;14(3):e003273. DOI: 10.1161/CIRCGEN.120.003273
  26. Adler A, et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation. 2020;141(6):418–428. DOI: 10.1161/CIRCULATIONAHA.119.043132
  27. Hosseini SM, et al. Reappraisal of reported genes for sudden arrhythmic death: evidence-based evaluation of gene validity for Brugada syndrome. Circulation. 2018;138(12):1195–1205. DOI: 10.1161/CIRCULATIONAHA.118.035070
  28. Walsh R, et al. Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. Eur Heart J. 2022;43(15):1500–1510. DOI: 10.1093/eurheartj/ehab687
  29. Renard M, et al. Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J Am Coll Cardiol. 2018;72(6):605–615. DOI: 10.1016/j.jacc.2018.04.089
  30. Lopes LR, et al. Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy. Eur Heart J. 2021;42(32):3063–3073. DOI: 10.1093/eurheartj/ehab424
  31. Arad M, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med. 2005;352(4):362–372. DOI: 10.1056/NEJMoa033349
  32. Merner ND, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82(4):809–821. DOI: 10.1016/j.ajhg.2008.01.010
  33. Crotti L, et al. Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry. Eur Heart J. 2019;40(35):2964–2975. DOI: 10.1093/eurheartj/ehz311
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  35. Altmann HM, et al. Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: elucidation of the triadin knockout syndrome. Circulation. 2015;131(23):2051–2060. DOI: 10.1161/CIRCULATIONAHA.115.015397
  36. Devalla HD, et al. TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. EMBO Mol Med. 2016;8(12):1390–1408. DOI: 10.15252/emmm.201505719
  37. Garcia CK, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001;292(5520):1394–1398. DOI: 10.1126/science.1060458
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  43. Garcia-Pavia P, et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021;42(16):1554–1568. DOI: 10.1093/eurheartj/ehab072
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Exercise Recommendations

Exercise Recommendation Matrix

Start from the baseline, not from the restrictions

Two Class I statements[2] apply before any condition-specific restriction below:

  1. Regular low- to moderate-intensity exercise is recommended in all able individuals with a cardiomyopathy.
  2. An individualised risk assessment for exercise prescription is recommended in every patient.

The matrix below qualifies that baseline for higher intensities and for competitive sport; it does not replace it. Deconditioning is a real harm, and a restriction should be a considered judgement about intensity, not a default.

In the matrix, "Restricted" means a weak recommendation requiring expert evaluation and shared decision-making, not a prohibition; "Contraindicated" reflects a Class III statement.

Condition Low Intensity Moderate Intensity Vigorous Intensity Competitive Sport
HCM Permitted Permitted
After individualised risk assessment		 Restricted
Low-risk, shared decision		 Restricted
Low-risk, expert evaluation
DCM Permitted Permitted
LVEF ≥50%; may be considered at LVEF 40–49%		 Restricted
May be considered if LVEF ≥50%, asymptomatic, optimally treated, no exercise-induced complex arrhythmia		 Restricted
Same conditions as vigorous; individualised
ACM Permitted Restricted
Recreational only; specialist review, shared decision		 Contraindicated Contraindicated
LQTS Permitted Restricted
Depends on type		 Restricted
Type & treatment dependent		 Restricted
Specialist review, on therapy
Brugada Permitted Permitted
Avoid dehydration		 Restricted
If asymptomatic		 Restricted
Asymptomatic: shared decision
CPVT Permitted Contraindicated Contraindicated Contraindicated
Marfan/TAAD Permitted Restricted
Root <40mm, non-contact		 Contraindicated
All root sizes		 Contraindicated
Contact/collision
Gene +ve / Pheno -ve
HCM		 Permitted Permitted Permitted
Class IIa		 Permitted
Class IIa / 2a; annual review
Gene +ve / Pheno -ve
DCM / NDLVC		 Permitted Permitted
Class IIa		 Permitted
Except LMNA, TMEM43		 Restricted
Shared decision
Gene +ve / Pheno -ve
ARVC		 Permitted Permitted Restricted
Avoidance may be considered (IIb)		 Restricted
Avoidance may be considered (IIb)

Sources: the ESC 2020 sports cardiology, ESC 2023 cardiomyopathy and ESC 2022 ventricular arrhythmia guidelines and the AHA/ACC 2024 HCM guideline (references 1–4). Where European and American guidance differ, both positions are given in the condition sections below.

Exercise Intensity Definitions

Light/Low Intensity

  • MET: <3 METs
  • Heart rate: <50% max HR
  • Examples: Walking slowly, bowling, golf (with cart), light housework
  • Can hold conversation easily

Moderate Intensity

  • MET: 3-6 METs
  • Heart rate: 50-70% max HR
  • Examples: Brisk walking, recreational swimming, cycling on flat terrain, doubles tennis, golf (carrying clubs)
  • Can talk but not sing

Vigorous Intensity

  • MET: >6 METs
  • Heart rate: 70-85% max HR
  • Examples: Running, singles tennis, competitive cycling, football, basketball, vigorous swimming
  • Difficult to talk comfortably

Competitive Sport

  • Organized team or individual sports
  • Regular training and competition
  • Performance-focused
  • Examples: Any sport at club, regional, or national level

Detailed Condition-Specific Recommendations

Hypertrophic Cardiomyopathy (HCM)

PERMITTED

  • Low intensity recreational exercise (walking, golf with cart, bowling)
  • Moderate-intensity recreational exercise (recreational swimming, doubles tennis, recreational cycling) after individualised risk assessment
  • Light resistance training (<50% MVC)
  • Vigorous or competitive sport may be considered in selected low-risk patients after comprehensive evaluation and shared decision-making (2024 AHA/ACC)

CONTRAINDICATED

  • Competitive or vigorous sport in patients with high-risk features (see below)
  • High-intensity exercise (running, intense cycling, vigorous swimming) unless low-risk and after shared decision-making
  • High static component sports (weightlifting, gymnastics)
  • Marathon, triathlon, CrossFit

Special considerations: Avoid activities that worsen the LVOT gradient (Valsalva, post-exercise).

High-risk features (any of the following should prompt specialist sports-cardiology review and will usually lead to restriction from vigorous and competitive activity, depending on the overall risk profile): Prior exertional syncope/presyncope, sustained VAs or cardiac arrest, family history of SCD in young relatives, severe LVH (≥30mm), extensive LGE (≥15% LV mass), severe LVOT obstruction (>50mmHg), apical aneurysm, LVEF <50%, NSVT, abnormal BP response to exercise, or HCM Risk-SCD ≥6%.

Dilated Cardiomyopathy (DCM)

PERMITTED

  • Low intensity exercise (all patients)
  • Moderate intensity if LVEF ≥50%; may be considered at LVEF 40–49%
  • Vigorous exercise may be considered if LVEF ≥50%, asymptomatic, optimally treated, with no exercise-induced complex arrhythmia
  • Competitive sport on the same conditions, individualised

CONTRAINDICATED

  • Vigorous or competitive sport if symptomatic, LVEF ≤40%, exercise-induced arrhythmias, or a pathogenic LMNA or TMEM43 variant (ESC 2023 Class III)
  • Any exercise during acute decompensation

Special considerations: Exercise capacity improves with appropriate medical therapy. Annual assessment recommended. LVEF 41–49% sits between the guideline statements (neither the permissive IIb nor the Class III applies): individualised specialist assessment weighing symptoms, arrhythmia burden, LGE, genotype and exercise testing. LMNA and TMEM43 variants: high-intensity and competitive sport not recommended regardless of LVEF; other arrhythmogenic genotypes (FLNC, DSP, RBM20, PLN) warrant a cautious, individualised approach.

Arrhythmogenic Cardiomyopathy (ACM)

PERMITTED

  • Low intensity recreational exercise only (walking, golf with cart)

RESTRICTED

  • Moderate-intensity recreational activity may be considered after specialist review and shared decision-making

GENERALLY AVOIDED

  • Competitive sport
  • Vigorous-intensity exercise
  • Endurance exercise (running, cycling, swimming)

Special considerations: Exercise accelerates disease progression in ARVC ("exercise paradox"); even moderate exercise may worsen the phenotype.

Long QT Syndrome (LQTS)

PERMITTED

  • Low intensity exercise (all genotypes)
  • Moderate intensity if on therapy, asymptomatic, QTc <500ms
  • Competitive sport may be considered after LQTS-specialist review if on therapy, no recent arrhythmic syncope, with an emergency action plan/AED[1]

GENERALLY AVOIDED

  • Unsupervised swimming/diving (LQT1); supervised swimming may be permitted after specialist evaluation
  • High intensity exercise (especially LQT1)

Genotype-specific: LQT1, caution with swimming/diving. LQT2, minimise sudden loud alarms/auditory triggers. LQT3, more permissive for exercise (events at rest/sleep). Beta-blocker therapy is foundational where tolerated, with specialist alternatives for intolerance or contraindication.

Brugada Syndrome

PERMITTED

  • Low-moderate intensity exercise if asymptomatic
  • Vigorous exercise may be considered if asymptomatic (no syncope, ventricular arrhythmia or cardiac arrest), after specialist assessment
  • Competitive sport possible if asymptomatic, shared decision-making

CONTRAINDICATED

  • Competitive sport if history of syncope or VF
  • Exercise in febrile illness (aggressive fever management essential)

Special considerations: Events typically occur at rest or during sleep, not exercise, so asymptomatic patients are treated more permissively than in other channelopathies. Avoid exercise during febrile illness and in settings likely to cause hyperthermia; avoid dehydration, excessive alcohol and the drugs listed at BrugadaDrugs.org.

Catecholaminergic Polymorphic VT (CPVT)

PERMITTED

  • Low intensity exercise only if well-controlled on therapy

CONTRAINDICATED

  • Competitive sports: strict avoidance
  • Moderate-vigorous exercise
  • Swimming
  • Any intense physical or emotional stress

Special considerations: Exercise/catecholamine-triggered, so the restrictions are the strictest of the channelopathies and apply even on high-dose beta-blocker plus flecainide. Compliance with therapy is critical.

Marfan Syndrome & Thoracic Aortic Aneurysm Disease (TAAD)

PERMITTED

  • Low intensity exercise (all patients)
  • Moderate intensity if aortic root <40mm
  • Non-contact sports if aortic dimensions stable

CONTRAINDICATED

  • Contact/collision sports (rugby, boxing, martial arts)
  • Isometric exercise (weightlifting)
  • Vigorous or competitive sport if aortic root >40mm

Special considerations: Exercise restrictions based on aortic dimensions. Annual imaging essential. Loeys-Dietz more aggressive (lower thresholds). Avoid Valsalva maneuvers and activities that spike blood pressure.

Genotype-Positive / Phenotype-Negative (G+/P-)

There is no single rule for genotype-positive, phenotype-negative individuals: the recommendation differs by phenotype[2] and by gene, and should involve the patient, the cardiologist and, where relevant, a sports physician.

PERMITTED

  • HCM: high-intensity exercise and competitive sport should be considered in those who seek to do so (Class IIa[2]); participation in competitive sport of any intensity is likewise rated reasonable (Class 2a[4])
  • DCM and NDLVC: moderate- and high-intensity exercise should be considered (Class IIa[2]), with the explicit exception of pathogenic LMNA and TMEM43 variants

REQUIRES INDIVIDUAL ASSESSMENT

  • ARVC families: avoidance of high-intensity exercise, including competitive sport, may be considered (Class IIb[2]) — a weak recommendation rather than a prohibition, and not distinguished by gene for ARVC
  • Channelopathy genotypes (e.g. RYR2 in CPVT, exercise-triggered LQTS genotypes) are assessed under ventricular-arrhythmia rather than cardiomyopathy criteria[3], and are handled in those condition sections

Surveillance: exercise permission does not change the need to watch for phenotype conversion. Annual assessment is recommended where competitive sport is undertaken[2]; otherwise follow that condition's usual screening interval (see its Follow-up section). Routine ambulatory ECG and exercise testing are not required in phenotype-negative individuals unless the family history indicates high risk or they form part of pre-participation screening (2024 AHA/ACC).

General Exercise Guidance

Adequate treatment: Optimize medical therapy before exercise.

Warning signs: Stop immediately if chest pain, palpitations, breathlessness, dizziness, or syncope.

Emergency plan: Patients and families should know CPR and have access to emergency services.

References & Review Date

Last reviewed: September 2026

  1. Pelliccia A, et al. 2020 ESC Guidelines on sports cardiology and exercise in patients with cardiovascular disease. Eur Heart J. 2021;42(1):17–96. doi:10.1093/eurheartj/ehaa605
  2. Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. doi:10.1093/eurheartj/ehad194
  3. Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. doi:10.1093/eurheartj/ehac262
  4. Ommen SR, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Circulation. 2024;149(23):e1239–e1311. doi:10.1161/CIR.0000000000001250

UK Driving Guidance

UK Driving - Patient Responsibilities

Whether DVLA notification is required depends on the condition, current symptoms and licence group, not a blanket rule — see the table below.

Where notification IS required, it is the PATIENT's responsibility to:

  • Notify DVLA of the diagnosis (online or by post)
  • Stop driving if told to do so or if the condition worsens
  • Attend reviews as required (typically 1-3 years)
  • Inform car insurance of the medical condition

Driving Rules at a Glance

Group 1 = car / motorcycle  ·  Group 2 = bus / lorry (HGV/PCV).

Cells: may drive conditional / restrictions barred / must not drive
Condition Group 1: Car / Motorcycle Group 2: Bus / Lorry (HGV/PCV)
HCM May drive if asymptomatic; DVLA notification generally not required unless another disqualifying feature is present.Symptomatic: notify DVLA, cease until 3 months symptom-free, EF >40%, no LVOT gradient >50 mmHg. Permitted only if LVOT <30 mmHg, wall <30 mm, no syncope, no NSVT, normal BP response to exercise, LVEF ≥45%.
DCM May drive if asymptomatic & LVEF >40%, annual review.Symptomatic / LVEF ≤40%: notify DVLA, cease if symptomatic. LVEF ≥45%, no symptomatic heart failure, no significant arrhythmia; annual review.
ARVC May drive if asymptomatic (no VT/VF/syncope, LVEF >40%).Symptomatic (VT/VF/syncope): cease until 3 months post-ablation or ICD. Barred if VT/VF, cardiac syncope, or LVEF <45%.
LQTS May drive if asymptomatic on therapy.Symptomatic: cease 3 months. No syncope/arrest, QTc <500 ms, on effective therapy; annual review.
Brugada May drive if asymptomatic.Symptomatic (syncope/arrest): cease, see ICD rules. Barred if any history of syncope or cardiac arrest.
CPVT May drive if asymptomatic.Symptomatic (syncope/arrest): cease, see ICD rules. Barred if any history of syncope or cardiac arrest.
Marfan / Aortopathy Individually assessed, BP control, aortic dimensions, no dissection history. Individually assessed, aortic size, BP control, absence of dissection history.
ICD (in situ) Primary prevention: 1 month off.
After appropriate shock (secondary prevention): 6 months off.
Inappropriate shock: 2 weeks (if cause fixed).		 Any ICD = permanent disqualification.

Summary of UK DVLA standards, each case is assessed individually. Always check the full DVLA cardiovascular fitness-to-drive guidance and, for HCM specifically, the HCM and driving page.

Group 2 Licensing (HGV/PCV): General Principles

A higher threshold than Group 1

A higher medical standard applies, reflecting the greater public-safety risk:

  • Burden of proof is on the applicant: must demonstrate fitness, not merely absence of disqualifying features
  • No syncope or near-syncope: any episode within 5 years is generally disqualifying
  • No symptomatic arrhythmia: must be controlled and stable
  • LVEF ≥45% required for most conditions (some require ≥50%)
  • Regular specialist review: typically annual; DVLA may issue 1-year licences
  • Any ICD = permanent disqualification
  • Pacemaker alone: may be compatible with Group 2 if underlying condition allows, subject to DVLA assessment

Key Points:

  • Returning to driving: DVLA will issue new licence when medical criteria met. No re-test required unless told otherwise. Patient must reapply if licence expired.
  • Temporary licences: DVLA may issue 1, 2, or 3-year licences requiring regular review rather than standard 10-year (Group 1) or 5-year (Group 2) licences.

References & Review Date

Last reviewed: September 2026

  1. Driver and Vehicle Licensing Agency. Cardiovascular disorders: assessing fitness to drive. In: Assessing fitness to drive: a guide for medical professionals. Swansea: DVLA. gov.uk/guidance/cardiovascular-disorders-assessing-fitness-to-drive
  2. Driver and Vehicle Licensing Agency. Hypertrophic cardiomyopathy and driving. gov.uk/hypertrophic-cardiomyopathy-and-driving
  3. Driver and Vehicle Licensing Agency. Contact DVLA (Drivers Medical Group). gov.uk/contact-the-dvla

Pregnancy in Inherited Cardiac Conditions

mWHO Classification of Cardiovascular Risk in Pregnancy
ClassRiskManagement
mWHO INo detectable increased maternal mortality; no/mild morbidity increaseLocal obstetric care; annual or once per pregnancy cardiology review
mWHO IISmall increased risk of maternal mortality; moderate morbiditySpecialist centre; cardiology review each trimester
mWHO IIISignificantly increased risk; expert counselling essentialExpert multidisciplinary Pregnancy Heart Team; monthly or more frequent review; delivery in tertiary centre
mWHO IVExtremely high maternal riskDetailed individualized counselling before conception; if pregnancy has already occurred, the Pregnancy Heart Team should discuss all options, including continuation with expert care and termination, with the decision led by the patient

The class shown for each condition below is a general starting point, not a fixed assignment. Per the 2025 ESC pregnancy guideline, actual risk should be individualized by a Pregnancy Heart Team using the specific risk modifiers listed for that condition (ventricular function, arrhythmia history, aortic dimensions, genotype, etc.), and can move within or across mWHO classes accordingly. All women with an inherited cardiac condition should have pre-pregnancy counselling from this team.[1][14]

Cardiomyopathies

Condition mWHO Class Key Risks Medications: Continue Medications: STOP / Avoid Delivery / Monitoring
HCM II–III
  • LVOTO
  • LVEF
  • Symptoms
 LVOTO can worsen with reduced preload; higher risk with reduced LVEF, symptomatic obstruction or prior arrhythmia.[1][2][14]
  • Beta-blockers (bisoprolol/metoprolol preferred)
  • Verapamil if beta-blocker intolerant
  • Disopyramide (1st trimester, uterotonic)
  • Vasodilators
  • Mavacamten (no data)
  • Echo every trimester, ± more if obstructive
  • Vaginal delivery preferred; shortened 2nd stage
  • Avoid hypovolaemia
  • Epidural preferred
DCM III–IV
  • LVEF
  • Functional class
 Risk rises with lower LVEF and worse functional class; prior peripartum cardiomyopathy carries a recognised recurrence risk. No single LVEF cut-off contraindicates pregnancy.[1][3][14]
  • Beta-blocker
  • Diuretic (furosemide) if pulmonary oedema
  • LMWH if LVEF <30%
  • Digoxin for rate control
  • ACEi/ARB/ARNI (teratogenic, stop pre-conception)
  • Spironolactone (antiandrogenic)
  • SGLT2i (limited data)
  • Amiodarone (last resort)
  • Echo monitoring individualized to severity (more frequent if reduced LVEF)
  • Delivery mode, timing and invasive monitoring decided on haemodynamic status at the time
ACM / ARVC II–III Pregnancy raises sympathetic tone and volume load, increasing arrhythmic risk, particularly with prior ventricular arrhythmia or significant RV/LV dysfunction; genotype informs risk where known.[1][2][4][14]
  • Beta-blockers (continue, max tolerated)
  • Sotalol if required (monitor QTc)
  • Flecainide (limited safety data, use only if essential)
  • Amiodarone (last resort)
  • Echo + Holter surveillance individualized to risk (typically each trimester or more often)
  • Epidural generally preferred (minimises catecholamines)
  • Delivery mode and timing set by functional status and arrhythmia history
  • Defibrillator available at delivery
Cardiac Amyloidosis III–IV Restrictive physiology can worsen in pregnancy and systemic involvement adds risk; ATTR amyloidosis in women of childbearing age is rare and the evidence base is very limited.[1][14]
  • Diuretics (careful)
  • Rate control
  • Tafamidis (no safety data, stop pre-conception)
  • Diflunisal
  • Patisiran/inotersen (no data)
 Expert MDT, individual assessment; very rare scenario.

Channelopathies

Condition mWHO Class Key Risks Medications: Continue Medications: STOP / Avoid Delivery / Monitoring
LQTS I–II Generally well tolerated. Postpartum risk is meaningfully higher, LQT2 in particular (within 9 months).[5][6] Risk increases with QTc >500ms or prior arrest; individualize surveillance intensity accordingly.[1][14]
  • Beta-blockers, essential; do not stop
  • Nadolol or propranolol preferred
  • Continue into postpartum (increased risk)
  • Monitor neonate for bradycardia/hypoglycaemia
 Check every drug against crediblemeds.org and the BNF/SmPC:
  • Ondansetron (recognised QT-prolongation risk)
  • Metoclopramide/cyclizine (not established as electrically neutral either)
  • Erythromycin, azithromycin
  • Some antifungals
  • Droperidol
  • Continuous ECG monitoring in labour
  • Avoid hypokalaemia (IV K⁺ supplementation)
  • Epidural preferred (reduces catecholamines)
  • Defibrillator immediately available
Brugada II–III Fever (common peripartum) can precipitate VF. Vagal predominance in labour may unmask a Brugada pattern. Higher risk if prior cardiac arrest or spontaneous type 1 ECG; individualize monitoring accordingly.[1][4][14]
  • Treat all fever aggressively with paracetamol
  • ICD if high-risk, should be implanted pre-pregnancy
  • Sodium-channel-blocking local anaesthetics: avoid or minimise high-dose/prolonged bupivacaine; ropivacaine is often preferred but also blocks sodium channels, so dose, duration and systemic absorption matter
  • Propofol: avoid prolonged or high-dose infusion; short procedural use is an anaesthetic/cardiology judgement with ECG monitoring
  • Check drugs at brugadadrugs.org
  • Continuous ECG monitoring
  • Defibrillator available
  • Epidural analgesia preferred; anaesthetic plan (agent and dose, ropivacaine commonly chosen) agreed antenatally with anaesthetics and cardiology
  • Temperature monitoring throughout labour and postpartum
CPVT II–III Labour pain/catecholamine surges may trigger VT/VF. Sympathetic activation should be minimised where possible. Beta-blocker adherence is important throughout.[1][4][14]
  • Beta-blockers (nadolol/propranolol), do not stop; maximise dose
  • Flecainide if already established add-on therapy
  • Avoid catecholamine-releasing GA agents (ketamine, ephedrine)
  • Avoid adrenaline-containing dental/local anaesthetics
  • Epidural analgesia strongly recommended, primary strategy to blunt sympathetic response
  • Continuous ECG + defibrillator
  • Avoid 2nd stage prolongation
Short QT Syndrome Not established
  • Very limited evidence
 Evidence too limited for a risk class; possible arrhythmia risk in labour and postpartum.[4][14]
  • Quinidine if established
  • Avoid drugs shortening QT
 Drugs shortening QT interval
  • Continuous ECG
  • Defibrillator available
  • Expert MDT (very limited evidence base)

Aortopathies & Connective Tissue Disorders

Condition mWHO Class Aortic Thresholds Medications Delivery Key Points
Marfan syndrome III–IV
  • Root diameter
  • Growth rate
  • Dissection history
 Risk rises substantially with a larger or growing aortic root or prior dissection; there is no single diameter cut-off. Consider prophylactic root surgery before conception.[1][7][8]
  • Continue: beta-blocker where indicated (bisoprolol/metoprolol/propranolol preferred; avoid atenolol in the 1st trimester, fetal growth restriction)
  • Stop pre-conception: losartan/ACEi (teratogenic)
  • Echo every 4–6 weeks
  • Root <40mm: vaginal delivery with epidural + shortened 2nd stage (avoid Valsalva)
  • Root 40–45mm: vaginal delivery with epidural and expedited 2nd stage, or caesarean, individualised by the Pregnancy Heart Team
  • Caesarean should be considered if root >45mm, rapid growth or prior dissection
  • Postpartum aortic imaging at 6 weeks and 6 months
  • Dissection risk persists postpartum
  • Breastfeeding: beta-blockers acceptable (monitor infant)
Loeys-Dietz syndrome Generally high risk
  • Gene-specific
  • Patient-specific
 Dissection can occur at smaller diameters than in Marfan and anywhere in the arterial tree; risk is gene- and patient-specific. Historical maternal-mortality figures (25–50%) overstate the risk for most LDS pregnancies.[1][9]
  • Continue: beta-blocker
  • Stop pre-conception: losartan/ACEi
  • ARB beneficial (TGF-β suppression) but teratogenic
  • Tertiary expert centre only
  • Delivery mode individual; avoid Valsalva
  • Full MDT including aortic surgery on standby
  • Even with prophylactic surgery pre-pregnancy, residual risk from non-root dissections persists
  • Pan-arterial imaging post-delivery
Vascular Ehlers-Danlos syndrome (vEDS) Generally high risk
  • Variant-specific
  • Vascular history
 Arterial, uterine or bowel rupture risk is elevated but not prohibitive; it depends on the specific COL3A1 variant and prior vascular history (a previous dissection or rupture confers materially higher risk).[14]
  • Continue: beta-blocker (celiprolol where already established)
  • Stop pre-conception: losartan/ACEi/ARB
  • Mode and timing individualised: labour tissue-injury risk versus caesarean haemorrhage risk in fragile tissue; caesarean is not automatically safer
  • Rupture risk persists for several weeks postpartum; keep specialist access and urgent-symptom advice in place
  • Counselling covers the realistic range of outcomes and all family-building options (see Genetic Counselling)
  • No validated review schedule or blood-pressure target; monitoring intensity set by the MDT
Bicuspid aortic valve (BAV) I–III
  • Depends on severity
 Pre-pregnancy aortic surgery should be considered in BAV at an aortic (root/ascending) diameter ≥50mm (ESC 2018; 2022 ACC/AHA); 45–50mm individualised with expert MDT. Caesarean is reasonable if the aorta is ≥45mm; vaginal delivery if <40mm and stable.[1][7][15]
  • Beta-blocker if aortopathy
  • Stop ACEi/ARB pre-conception if used
  • Echo each trimester
  • If severe AS or AR: discuss valve intervention pre-pregnancy
  • Vaginal delivery possible in mild-moderate disease
  • Screen for coarctation (increased BP in pregnancy if coarctation present)
  • Genetics referral / aortopathy gene panel if syndromic features, early or disproportionate aortic dilatation, dissection, or family history of thoracic aortic disease
Turner syndrome III–IV
  • If aortic disease
 BAV in ~30%; coarctation ~10%; aortic dilatation assessed by aortic size index (ASI >2.5 cm/m² = high risk; pregnancy generally not advised). Assess pre-pregnancy with CMR or CT and weigh other risk modifiers (BAV, coarctation, hypertension).[1]
  • Antihypertensives
  • Avoid ACEi/ARB
  • Aortic imaging pre-pregnancy and each trimester
  • If ASI >2 cm/m²: tertiary centre delivery
  • Pregnancy usually via oocyte donation
  • Obstetric complications high (hypertension, pre-eclampsia)
  • Postpartum aortic monitoring

Storage & Infiltrative Conditions

Condition mWHO Class Key Risks Medications Monitoring & Delivery
Fabry disease II
  • If stable cardiac/renal function
 Generally well tolerated if no significant cardiac or renal involvement. CKD increases obstetric risk. Neuropathic pain may worsen.[12]
  • Continue: ERT (agalsidase alfa 0.2mg/kg q2wks or agalsidase beta 1mg/kg q2wks); continue after specialist discussion (reassuring case-series evidence)[12]
  • Avoid: migalastat (inadequate safety data)
  • Stop ACEi/ARB pre-conception
  • Echo + renal function each trimester
  • Vaginal delivery generally possible
  • Monitor neonate if ERT continued (no known neonatal effects)
Pompe disease II–III Respiratory involvement may compromise pregnancy, assess FVC. Cardiac involvement usually mild in late-onset forms.
  • Alglucosidase alfa (ERT), limited data; generally continued in specialist centres
  • Respiratory support if needed
  • Respiratory function assessment essential
  • May require assisted ventilation
  • MDT including respiratory medicine

Neuromuscular Conditions

Condition mWHO Class Key Risks Medications Monitoring & Delivery
DMD/BMD female carriers II–III
  • If LV dysfunction
 ~30% of female DMD carriers have LV dysfunction, often subclinical.[10] Pregnancy can unmask or worsen cardiomyopathy; obstetric complications may be higher with skeletal muscle involvement.[1][14]
  • Continue: beta-blocker if LV dysfunction present
  • Stop pre-conception: ACEi/ARB/eplerenone
  • SGLT2i: avoid (limited data)
  • Echo at booking + each trimester
  • Vaginal delivery generally possible; epidural preferred
  • Monitor respiratory function if skeletal myopathy present
Myotonic dystrophy type 1 (DM1) II–III Cardiac arrhythmias (AV block, VT), uterine atony (prolonged labour), respiratory compromise.[11] Maternal and congenital myotonic dystrophy risk in infant (anticipation, maternal transmission worse).[1]
  • ICD/pacemaker if indicated pre-pregnancy
  • Avoid drugs worsening myotonia
  • ECG/Holter each trimester
  • Anaesthetic risk, detailed assessment essential
  • Oxytocin for uterine atony; PPH risk
  • Neonatal assessment for congenital DM1
Friedreich ataxia II–III Hypertrophic or dilated cardiomyopathy; arrhythmias. Neurological disease affects mobility and labour management.[1]
  • Continue cardiac medications (beta-blocker if LV dysfunction)
  • Omaveloxolone: stop pre-conception (no safety data)
  • Cardiology + neurology MDT
  • Echo each trimester
  • Regional anaesthesia may be limited by scoliosis; anaesthetic assessment essential

Cardiac Drug Safety in Pregnancy: Quick Reference[1][14]

Drug / Class ICC Indications Pregnancy Safety Recommendation
Beta-blockers (bisoprolol, metoprolol, propranolol, nadolol, atenolol) HCM, DCM, ARVC, LQTS, CPVT, Marfan Generally considered compatible, and usually continued where indicated. They cross the placenta, so monitor fetal growth and the neonate for bradycardia and hypoglycaemia. Atenolol associated with IUGR (avoid in 1st trimester).[1] Bisoprolol/metoprolol/propranolol preferred. Continue, do not stop
Verapamil HCM (if beta-blocker intolerant) Generally acceptable. May cause neonatal bradycardia/hypotension near term. Avoid high doses. Acceptable if beta-blocker not tolerated; lowest effective dose
Sotalol ARVC Acceptable safety profile in pregnancy. Monitor fetal HR. QTc monitoring required. Acceptable, monitor fetal and maternal QTc
Diuretics (furosemide) DCM, HF Generally acceptable if used judiciously. Avoid excessive dose, which may reduce uteroplacental perfusion. Acceptable for pulmonary oedema; use minimum effective dose
LMWH (enoxaparin, dalteparin) DCM, AF, mechanical valves Drug of choice for anticoagulation in pregnancy, does not cross placenta Preferred anticoagulant throughout pregnancy; requires dose adjustment and monitoring
Disopyramide HCM Uterotonic, may stimulate contractions (especially 1st trimester). Limited data overall. Avoid in 1st trimester; use only if benefit > risk with expert advice
Flecainide ARVC, CPVT Limited human data. Used for fetal arrhythmias, some fetal safety data. Avoid unless essential. Use only if essential; specialist advice required
Spironolactone DCM Antiandrogenic, animal studies show feminisation of male foetus at high doses Avoid; switch to eplerenone (less antiandrogenic) or stop if safe
SGLT2 inhibitors (dapagliflozin, empagliflozin) DCM No adequate human data; animal embryotoxicity concerns Stop pre-conception or as soon as pregnancy confirmed
Migalastat (Galafold) Fabry disease No human data Stop pre-conception; switch to ERT if treatment required
Warfarin Mechanical heart valves, AF Warfarin embryopathy <12 weeks; fetal intracranial haemorrhage risk. Acceptable weeks 14–34 for mechanical valves if dose ≤5mg/day. Mechanical valve specific use only; avoid <12 weeks and near term; switch to LMWH peripartum
ACE inhibitors (ramipril, lisinopril, perindopril) DCM, Duchenne Teratogenic, renal agenesis, oligohydramnios, neonatal renal failure, skull ossification defects (2nd/3rd trimester).[1] STOP pre-conception; switch to alternative
ARBs (losartan, candesartan, valsartan) Marfan, DCM, Fabry Same fetotoxicity as ACEi, contraindicated from conception.[1] STOP pre-conception
Sacubitril/valsartan (ARNI) DCM Valsartan component fetotoxic; sacubitril, no human data STOP pre-conception; switch to beta-blocker ± diuretic
Amiodarone ARVC, DCM Fetal hypothyroidism, goitre, IUGR, premature birth, neonatal bradycardia. High iodine content. Last resort only.[1] Avoid, use only for life-threatening arrhythmia uncontrolled by other agents
Mavacamten HCM (obstructive) No human data; animal reproductive toxicity.[2] Stop pre-conception; effective contraception required (CYP2C19 metabolism, drug holidays)
DOACs (apixaban, rivaroxaban, edoxaban, dabigatran) AF in various conditions Fetal and embryo toxicity in animal studies; no human safety data; cross placenta.[1] Contraindicated in pregnancy, switch to LMWH pre-conception

Pre-Pregnancy Genetic Counselling

Key Principles
  • Genetic counselling should be offered to all patients with an ICC and their partners before conception.[1][13]
  • Ideally initiated at diagnosis, not at point of pregnancy planning (allows time for family decisions)
  • Involves: inheritance pattern, risk to offspring, available reproductive options, implications for family members
  • Refer to regional clinical genetics service; joint cardiac-genetics clinic optimal

Inheritance Patterns & Offspring Risk by Condition

Condition Inheritance Risk to Offspring Penetrance Notes
HCM (MYBPC3, MYH7) Autosomal dominant 50% per child Variable, MYBPC3 ~65% by age 50; MYH7 >95%.[2] De novo mutations ~5%. Cascade testing of 1st-degree relatives.
DCM (LMNA, TTN, FLNC etc.) Autosomal dominant (most) 50% per child LMNA >90%; TTN 30–40%; variable by gene.[2] Early cardiac surveillance in gene-positive offspring. LMNA/FLNC, higher arrhythmic risk that may justify ICD consideration earlier than conventional thresholds, individualised by risk model/phenotype.
ACM / ARVC (PKP2, DSP etc.) Autosomal dominant (most); AR (Naxos/Carvajal) 50% per child (AD); 25% (AR) 30–50% (PKP2); >90% males (TMEM43) Exercise restriction advice for gene-positive offspring. Clinical screening from childhood.
LQTS (KCNQ1, KCNH2, SCN5A) Autosomal dominant (Romano-Ward); AR (Jervell-Lange-Nielsen, deaf) 50% per child 25–75% (AD); ~100% (AR) Neonatal ECG ± genetic testing. Beta-blocker started promptly if QTc prolonged. JLN: if both parents carry KCNQ1/KCNE1 variants, 25% risk of severe phenotype in offspring.
Brugada (SCN5A) Autosomal dominant; incomplete penetrance 50% per child 15–35%; male-predominant expression ~70% genetically elusive. Cascade ECG ± genetic testing in family. Fever protocols for gene-positive children.
CPVT (RYR2, CASQ2) RYR2: autosomal dominant; CASQ2: autosomal recessive 50% (RYR2); 25% affected, 50% carrier (CASQ2) >80% (RYR2) Exercise stress test in gene-positive children. Start beta-blocker immediately if symptomatic.
Fabry disease (GLA) X-linked (GLA on Xq22) Affected (hemizygous) father: sons 100% unaffected (receive the Y chromosome); daughters 100% heterozygous for the familial GLA variant, with variable expression, many develop disease. Heterozygous mother: 50% of sons hemizygous and affected, 50% of daughters heterozygous. Males: near 100%. Females: variable (lyonisation). Heterozygous females are not simply carriers: expression is variable and many develop significant disease. Where the familial GLA variant is known, at-risk male infants should be offered early testing (hemizygous males are usually affected).[12]
Marfan (FBN1) Autosomal dominant 50% per child Near 100% (high penetrance, variable expressivity).[8] ~25% de novo. Clinical assessment of offspring at birth and periodically. Early beta-blocker if aortic dilation.[8]
Loeys-Dietz (TGFBR1/2, SMAD3, TGFB2/3) Autosomal dominant 50% per child High but variable by gene and variant Full aortic imaging of gene-positive offspring from early childhood. More aggressive than Marfan.
Duchenne (DMD) X-linked recessive Female carrier: 50% of sons affected, 50% of daughters carrier Males: ~100%. Females: carriers may have cardiac involvement (~30%). Carrier females: cardiac surveillance.

Reproductive Options for Couples with ICC

Option Description Considerations
Natural conception + postnatal testing Conceive naturally; test child after birth (or at appropriate age) Simple; no intervention. Child will require surveillance if gene-positive. Discuss age of testing (respect child autonomy for adult-onset conditions).
Prenatal diagnosis (PND): CVS or amniocentesis Chorionic villus sampling (10–13 wks) or amniocentesis (15–20 wks) for fetal genetic testing Enables decision whether to continue pregnancy. Risk of miscarriage ~0.5–1%. Available on NHS. Psychological impact of result significant.
Preimplantation genetic testing, monogenic (PGT-M) IVF with embryo biopsy + genetic testing before transfer; only unaffected embryos implanted.[13] Avoids pregnancy termination decision. Requires IVF (cycles, cost, success rate ~25–40%/cycle). HFEA licensed centre required. Lead time ~12 months. NHS-funded in some regions for high-penetrance conditions.
Donor gametes (sperm or egg donation) Use unaffected donor, removes genetic transmission risk from one parent Eliminates transmission from carrier parent. Requires donor services; legal and psychological counselling. Not suitable if both parents carry pathogenic variants.
Adoption / fostering Parenting without genetic transmission Valid option, discuss without bias. Process can be lengthy. No medical contraindication from ICC itself.

PGT-M requires identification of the familial pathogenic variant in advance. Couples should be referred to clinical genetics and reproductive medicine well before planned conception. NHS funding criteria vary by region and condition penetrance.

References & Review Date

Last reviewed: September 2026

  1. Regitz-Zagrosek V, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018;39(34):3165–3241. DOI: 10.1093/eurheartj/ehy340
  2. Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194
  3. McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726. DOI: 10.1093/eurheartj/ehab368
  4. Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. DOI: 10.1093/eurheartj/ehac262
  5. Seth R, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol. 2007;49(10):1092–1098. DOI: 10.1016/j.jacc.2006.09.054
  6. Rashba EJ, et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. Circulation. 1998;97(5):451–456. DOI: 10.1161/01.CIR.97.5.451
  7. Erbel R, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases. Eur Heart J. 2014;35(41):2873–2926. DOI: 10.1093/eurheartj/ehu281
  8. Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47(7):476–485. DOI: 10.1136/jmg.2009.072785
  9. MacCarrick G, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16(8):576–587. DOI: 10.1038/gim.2014.11
  10. McNally EM, et al. Contemporary Cardiac Issues in Duchenne Muscular Dystrophy. Circulation. 2015;131(18):1590–1598. DOI: 10.1161/CIRCULATIONAHA.114.015151
  11. Groh WJ, et al. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med. 2008;358(25):2688–2697. DOI: 10.1056/NEJMoa062800
  12. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. DOI: 10.1186/1750-1172-5-30
  13. Musunuru K, et al. Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association. Circ Genom Precis Med. 2020;13(4):e000067. DOI: 10.1161/HCG.0000000000000067
  14. De Backer J, Haugaa KH, et al. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy. Eur Heart J. 2025;46(43):4462–4568. DOI: 10.1093/eurheartj/ehaf193
  15. Isselbacher EM, et al. 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease. Circulation. 2022;146(24):e334–e482. DOI: 10.1161/CIR.0000000000001106

Resources

Cardiomyopathies

ESC Guidelines for the Management of Cardiomyopathies

European Society of Cardiology, 2023

View Guideline →

AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy

AHA / ACC / AMSSM / HRS / PACES / SCMR, 2024

View Guideline →

HRS Expert Consensus Statement on Evaluation, Risk Stratification, and Management of Arrhythmogenic Cardiomyopathy

Heart Rhythm Society, 2019

View Guideline →

Heart Failure

ESC Guidelines for the Management of Heart Failure

European Society of Cardiology, 2026

View Guideline →

Arrhythmias & Channelopathies

ESC Guidelines for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death

European Society of Cardiology, 2022

View Guideline →

HRS/EHRA/APHRS/LAHRS Expert Consensus Statement on the Management of Inherited Primary Arrhythmia Syndromes

Heart Rhythm Society / EHRA / APHRS / LAHRS, 2022

View Guideline →

Aortopathies

ESC Guidelines for the Management of Peripheral Arterial and Aortic Diseases

European Society of Cardiology, 2024

View Guideline →

ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease

ACC / AHA, 2022

View Guideline →

Pregnancy

ESC Guidelines for the Management of Cardiovascular Disease and Pregnancy

European Society of Cardiology, 2025

View Guideline →

Sports Cardiology & Exercise

ESC Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease

European Society of Cardiology, 2020

View Guideline →

Device Therapy

ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy

European Society of Cardiology, 2021

View Guideline →

Genetic Testing

ACMG/AMP Standards and Guidelines for the Interpretation of Sequence Variants

American College of Medical Genetics and Genomics / Association for Molecular Pathology, 2015

View Guideline →

UK Resources

National Genomic Test Directory

NHS England, version 9, 2026/27

View Guideline →

Assessing Fitness to Drive: Cardiovascular Disorders

Driver and Vehicle Licensing Agency (DVLA)

View Guideline →

Last reviewed: September 2026

Clinical Decision Calculators

HCM Risk-SCDHCM 5-year sudden cardiac death risk, to guide primary-prevention ICD decisions on this site NB:Derived in patients aged 16 and over without prior cardiac arrest or sustained VT ARVC Risk CalculatorARVC 5-year risk of sustained ventricular arrhythmia arvcrisk.com NB:Derived in definite, predominantly right-dominant ARVC; performs less well in left-dominant disease, and poorly in desmoplakin carriers — use the DSP Risk Score below LMNA-risk VTALMNA 5-year risk of life-threatening ventricular tachyarrhythmia in laminopathy lmna-risk-vta.fr NB:Wahbi et al. (Circulation 2019). External validation found high sensitivity but low specificity, over-predicting arrhythmic risk particularly in men DSP Risk ScoreDSP 5-year risk of sustained ventricular arrhythmia in desmoplakin variant carriers dsp-risk.com NB:Primary prevention only, in carriers with no prior sustained VA. Developed because the ARVC risk calculator performs poorly in DSP carriers Cardiac Amyloidosis StagingATTR Gillmore / NAC stages I–III from NT-proBNP and eGFR mdcalc.com NB:For transthyretin amyloidosis. AL amyloidosis is staged separately by the revised Mayo system Seattle Heart Failure ModelDCM 1-, 2- and 5-year survival, to time transplant assessment and advanced HF referral depts.washington.edu NB:Derived from PRAISE-1, which pre-dates ARNI and SGLT2 inhibitors; over-estimates mortality in patients on contemporary foundational medical therapy Corrected QT (QTc)LQTS Bazett, Fridericia, Framingham and Hodges corrections mdcalc.com NB:Fridericia preferred at heart rates below 50 or above 90 bpm; Bazett remains the most widely reported Aortic Root Z-scoreMarfan BSA-adjusted aortic root Z-score (≥2 = dilated) marfan.org NB:This is the adult tool, for patients over 15. The Marfan Foundation hosts a separate paediatric calculator

Professional Societies

British Inherited Cardiac Conditions Society UK professional society for inherited cardiac conditions biccs.org.uk European Society of Cardiology Clinical practice guidelines and educational resources escardio.org American College of Cardiology Clinical guidelines, tools and educational content acc.org Heart Rhythm Society Cardiac electrophysiology and arrhythmia management hrsonline.org British Cardiovascular Society UK professional body for cardiovascular healthcare britishcardiovascularsociety.org.uk

Patient & Charity Organisations

Cardiomyopathy UK Support and information for people affected by cardiomyopathy cardiomyopathy.org Cardiac Risk in the Young (CRY) Working to reduce young sudden cardiac death c-r-y.org.uk SADS UK Support for families affected by sudden arrhythmic death sadsuk.org.uk The Marfan Foundation Marfan syndrome and related connective tissue disorders marfan.org

Genetics Resources

NHS England National Genomic Test Directory NHS-commissioned genomic tests and their eligibility criteria england.nhs.uk ClinGen: Clinical Genome Resource Gene–disease validity and variant interpretation guidance clinicalgenome.org ClinVar Submitted variant classifications with review status ncbi.nlm.nih.gov OMIM: Online Mendelian Inheritance in Man Catalogue of human genes and genetic disorders omim.org

Last reviewed: September 2026

Specialist inherited cardiac conditions services across the UK, grouped by regional network. Hover the map to see the networks; click a region to pin it. Details are drawn from the BICCS ICC Service Directory – always confirm current referral routes with the receiving centre.

All regions
CentreLead clinicianContactServicesPaeds
CM cardiomyopathyIA inherited arrhythmia / channelopathyAo aortopathyNM neuromuscular / mitochondrialSADS SADS / family screening

Last reviewed: September 2026 · Source: BICCS ICC Service Directory (accessed September 2026). Regions follow the BICCS hub structure: four Scottish networks, Northern Ireland, Wales and the nine English regions.

The key studies behind practice in each inherited cardiac condition, drawn to scale by the number of participants.

Area = number of participants.

Randomised trial   Observational study, registry or meta-analysis.

Not drawn (no landmark outcome study): NDLVC, Loeys-Dietz, mitochondrial disease.

StudyYearnDesignWhat it showedSource

Last reviewed: September 2026 · Every DOI resolved on Crossref and the sample sizes and findings checked against the abstracts, September 2026.

0 questions

Last reviewed: September 2026 · 184 questions, 13 conditions.

About ICCnotes

ICCnotes is a clinical reference on inherited cardiac conditions (ICC), covering genetics, diagnosis, risk stratification, follow-up, exercise and UK driving (DVLA) guidance, pregnancy, and practical management across 25 conditions. It is written for clinicians and trainees.

Disclaimer

ICCnotes is a set of referenced working notes for healthcare professionals, arranged for looking something up in clinic rather than learning a subject from scratch. It summarises and cites the guidelines but does not stand in for them: read the source document before acting on a recommendation, verify drug doses and thresholds against the current SmPC/BNF, and apply independent clinical judgement, specialist advice and local policy. Do not enter patient-identifiable data into any linked external calculator.

Authorship and review

ICCnotes was created by Dr Zakariye Ashkir (MBChB MRCP DPhil), a UK-based cardiologist working in inherited cardiac conditions and cardiac imaging.

The content is updated as guidelines and evidence change, each condition carries its own review date, and it is currently undergoing peer review.

Every clinical statement carries an inline citation, given in full with a DOI link wherever one exists, so a claim can be traced back to the paper it came from. Content is drawn from current ESC, AHA/ACC, HRS, NICE and BHRS guidance and the primary literature underpinning it. Where the evidence is weak, or the guidelines disagree, that is said rather than smoothed over.

Contributing reviewers

  • Dr Mohamed Abid Akhtar MBBS iBSc MRCP MSc (Oxon), Barts Heart Centre, London
  • Dr Viren Ahluwalia MBBS MRCP, Imperial College London

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ICCnotes is free to use, with no paywall, registration or advertising. It receives no pharmaceutical or commercial funding, nothing on it is sold, and no commercial party influences its content.

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Last reviewed September 2026