Genetic Testing in Cardiomyopathy

Definition

Genetic testing in cardiomyopathy refers to the systematic application of DNA sequencing — primarily multigene panel testing — to identify disease-causing variants in patients with HCM, DCM, ARVC, RCM, or LVNC phenotypes. Its goals are to establish a molecular aetiology, inform prognosis, guide gene-specific management, and enable cascade testing of at-risk family members.

Indications and Testing Strategy

Rationale for Genetic Testing

• Cardiomyopathies are medically actionable genetic conditions: established treatments can improve survival, reduce morbidity, and enhance quality of life once disease is detected — making identification of genetic risk compelling (sources/genetic-cmp-jcf-2018 — very high)
• The first clinical manifestation may be sudden cardiac death; cascade screening identifies asymptomatic at-risk relatives before a sentinel event (sources/genetic-cmp-jcf-2018 — very high)
• Gene-specific management recommendations exist that cannot be derived from phenotype alone — e.g., LMNA warrants early ICD consideration before LVEF <35%; LAMP2/PRKAG2/GLA are genocopies of sarcomeric HCM with distinct management (sources/genetic-cmp-jcf-2018 — very high)
• Genetic testing has been shown to be cost-effective for HCM (Australia and United States) (sources/genetic-cmp-jcf-2018 — very high)
• ESC 2023 endorses genetic testing as part of the aetiological evaluation of all cardiomyopathy phenotypes; minimum DCM gene panel is a Class I recommendation (sources/esc-cmp-2023 — very high)
• AHA 2022: referral for genetic counselling and testing is "reasonable" (COR 2a) in select nonischemic cardiomyopathy patients; genetic testing of 1st-degree relatives is COR I (sources/HF-AHA-2022 — very high)

Who to Test — Proband Selection

• Testing should be initiated on the most clearly affected family member with the most definitive diagnosis and most severe manifestations — maximises diagnostic yield and chance of detecting multiple co-existing variants (sources/genetic-cmp-jcf-2018 — very high)
• If the ideal proband is unavailable or unwilling, comprehensive testing of another affected family member is appropriate
• For sudden death with autopsy diagnosis of cardiomyopathy: post-mortem genetic testing (molecular autopsy) facilitates cascade testing in living relatives (sources/genetic-cmp-jcf-2018 — very high; sources/HCM-AHA-2024 — high)

When to Test

• Genetic testing is recommended at the time of a new cardiomyopathy diagnosis; it can be conducted at any time after diagnosis (sources/genetic-cmp-jcf-2018 — very high)
• Retesting is appropriate if test sensitivity has meaningfully increased (suggested threshold: 5–10% improvement); particularly relevant for DCM as new genes (TTN, BAG3) have been added (sources/genetic-cmp-jcf-2018 — very high)
• Variant reclassification should prompt re-contact of affected families; periodic re-evaluation every 2–3 years is Class I per AHA 2024 HCM guideline (sources/HCM-AHA-2024 — high)

How to Test — Multigene Panels

• Multigene panel testing is the current standard of care — recommended over serial single-gene testing due to genetic heterogeneity of cardiomyopathies, improved efficiency, and cost reduction (sources/genetic-cmp-jcf-2018 — very high)
• Next-generation sequencing (NGS) allows sequencing of dozens of disease-relevant genes simultaneously at lower cost; cost continues to decline (sources/genetic-cmp-jcf-2018 — very high)
• Panel composition varies between laboratories; clinicians must review gene content before ordering, ensuring inclusion of the most relevant core genes
• Larger panels increase the probability of identifying a molecular aetiology but also increase VUS burden in proportion to the number of genes tested
• Copy number variants (structural variants) account for <1% of cardiomyopathy cases and may require dedicated analysis beyond standard NGS (sources/genetic-cmp-jcf-2018 — very high)
• ESC 2021 HF guidelines specify a minimum DCM gene panel as a Class I recommendation: TTN, LMNA, MYH7, TNNT2, TNNI3, MYBPC3, RBM20, PLN, SCN5A, BAG3, ACTC1, nexilin, TPM1, VCL (sources/HF-ESC-2021 — very high)

Diagnostic Yield

Diagnostic Yields by Cardiomyopathy Phenotype

• ESC 2023 reports ~40–60% HCM yield and ~30% DCM yield, consistent with HFSA 2018 estimates (sources/esc-cmp-2023 — very high)
• Early-onset AF: genetic testing of cardiomyopathy/arrhythmia panel yields P/LP variants in ~10% overall; TTN most common, but DCM genes (LMNA, PKP2) predominate (sources/eoaf-jama-2021 — high)

Real-World Diagnostic Yield — Combined Cardiomyopathy + Arrhythmia Panel (JAMA Cardiology 2022)

A large real-world cohort study (n=4,782) using a no-charge sponsored combined panel (up to 150 genes; Invitae Corporation) with broad inclusion criteria (any level of clinical suspicion) provides the most comprehensive yield data across all cardiomyopathy and arrhythmia subtypes (sources/genetic-yield-jama-card-2022 — high):

• Overall diagnostic yield: 19.9% — lower than prior enriched referral cohorts (~30%); reflects permissive inclusion (any level of suspicion)
• If restricted to high-suspicion patients only (per AHA guidance): 14.4% of positives would have been missed — 9% of low-suspicion patients still had a positive result

• Most common P/LP genes: MYBPC3 (16.7%), TTN (11.7%), MYH7 (9.0%)
• VUS burden: 51.2% of all patients had ≥1 VUS in absence of any P/LP variant — the principal trade-off of broad panel testing; rates are higher in non-White patients due to underrepresentation in reference databases

Combined vs. Disease-Specific Panel Testing

• Among 689 patients with a single specific disease indication, combined testing produced 75 additional diagnoses (10.9%) that disease-specific panels would have missed (sources/genetic-yield-jama-card-2022 — high):
  • 44.0% of gained diagnoses were within-category (different cardiomyopathy subtype than indicated)
  • 36.0% of gained diagnoses were cross-category (arrhythmia indication → cardiomyopathy gene finding, or vice versa)
  • LVNC had the highest proportion of missed diagnoses (87.5%; p=0.001) — reflects poorly defined genetic landscape of this entity
  • SCN5A exemplifies phenotypic overlap: patients with SCN5A positive findings had mixed referral indications (arrhythmia subtypes AND cardiomyopathy subtypes), confirming the same gene can drive both phenotypes
• Combined testing was statistically superior to disease-specific testing for total cohort (P=.02)
• The study also found that 5% of DCM patients harbour variants in both ion channel and cardiomyopathy genes (Li et al.), and 10% of early-onset AF patients harbour variants in cardiomyopathy genes (Yoneda et al.) — providing independent support for combined panels

Clinical Implications of Results

Clinical Management Implications of Genetic Diagnoses

• 66% of positive results (630/954) in the combined panel cohort had direct clinical management implications (sources/genetic-yield-jama-card-2022 — high):
  • Sarcomeric HCM genes (ACTC1, MYL2, MYBPC3, MYH7, MYL3, TNNI3, TNNT2, TPM1): 279 patients (29.2% of positives) — earlier monitoring for AF, VT, HF vs. non-sarcomeric HCM
  • LAMP2: 4 patients (0.4%) — rapid deterioration, early cardiac transplant consideration
  • Heightened arrhythmia risk genes (ABCC9, DES, DSP, FLNC, LMNA, PLN, RBM20, RYR2, SCN5A, TTN): 300 patients (31.4%) — more intensive cardiac monitoring and/or device intervention
  • Targeted therapy genes (GAA, GLA, TTR): 57 patients (6.0%) — enzyme replacement therapy (GAA/GLA) or TTR stabilisers/inhibitors
• Among all patients tested (not just positives): 1 in 8 (13.2%) had a result informing prognosis or management

Specific Gene Highlights

TTN (Titin):

• TTN truncating variants (TTNtv) are the most common genetic finding in DCM (10–20%); TTNtv in constitutive exons is associated with modest decrement in LV function even in population-based cohorts — may function as a risk allele rather than fully penetrant pathogenic variant (sources/genetic-cmp-jcf-2018 — very high)
• Non-segregating TTNtv cases have been identified, complicating P/LP classification (sources/genetic-cmp-jcf-2018 — very high)
• TTNtv also found in peripartum cardiomyopathy (rates similar to DCM), alcoholic CMP (13.5%), and cancer therapy-related CMP (sources/esc-cmp-2023 — very high)

LMNA:

• Second most common DCM gene (5.5%); highest risk for malignant VA among all cardiomyopathy genes
• Gene-specific ICD indication: early ICD should be considered before LVEF <35% due to high VA risk during progressive conduction disease phase (sources/genetic-cmp-jcf-2018 — very high)
• Specific risk calculator: LMNA risk-VTA (lmna-risk-vta.fr) (sources/esc-cmp-2023 — very high)

HCM genocopies (important to distinguish — different management):

• LAMP2 (Danon disease): severe HCM + cardiac preexcitation + intellectual disability; cardiac transplant often required; female carriers develop DCM or HCM in 2nd–3rd decade
• GLA (Fabry disease): HCM phenocopy; cardiac variant presents ≥40 yr; low native T1 on CMR; ERT is disease-modifying especially for males
• PRKAG2: non-lysosomal glycogen accumulation + WPW + heart block
• GAA (Pompe disease): infantile HCM; enzyme assay mandatory in any infant with HCM; ERT time-critical
• See entities/Fabry-Disease, concepts/Fabry-Cardiomyopathy, and entities/ATTR-Amyloidosis for full detail.

Cascade and Postmortem Testing

Cascade Genetic Testing After Proband Identification

• Once a P/LP variant is identified in a proband, cascade genetic testing is recommended for all at-risk 1st-degree relatives (sources/genetic-cmp-jcf-2018 — very high)
• Genotype-negative relative for a known P/LP variant: risk substantially reduced; can be discharged from serial phenotype surveillance after baseline evaluation; counsel to return if symptoms develop (sources/genetic-cmp-jcf-2018 — very high; sources/esc-cmp-2023 — very high)
• Genotype-positive, phenotype-negative relative: counsel on penetrance and expressivity; serial phenotypic surveillance at intervals (see Guideline 2 of HFSA 2018)
• VUS identified in proband: do NOT use for cascade genetic testing of relatives; phenotypic family evaluation instead (sources/genetic-cmp-jcf-2018 — very high; sources/HCM-AHA-2024 — high)
• Pre- and post-test genetic counselling is mandatory for cascade testing

Postmortem (Molecular Autopsy) Genetic Testing

• 190 postmortem cases (4.0% of the combined panel cohort); median age at death 26 years (sources/genetic-yield-jama-card-2022 — high)
• Positive rate in postmortem: 9.5% (lower than living cohort); 54.7% uncertain; 35.8% negative/carrier
• Cascade testing was performed in 61.1% of postmortem-positive cases vs. 32.1% of living-positive cases — underscoring the urgency of family testing after sudden death
• 40.9% of family members of postmortem-positive patients were themselves positive on cascade testing
• Collect tissue samples at autopsy; select panels guided by autopsy findings and surviving family members' clinical results (sources/genetic-test-aha-2020 — high)

Variant Interpretation

Variant Interpretation and Classification

• ACMG/AMP 2015 classification: Pathogenic (P), Likely Pathogenic (LP), VUS, Likely Benign, Benign — now the universal standard for clinical reporting (sources/genetic-cmp-jcf-2018 — very high)
• VUS frequency is high and increases with larger panels; most novel variants in any gene — even well-established ones — will initially be classified as VUS
• Segregation analysis: tracking a VUS through family members with cardiomyopathy is the most powerful tool for reclassification to LP/P
• Bilineal disease complicates segregation analysis (both parents may carry different variants)
• Resources: ClinVar, ClinGen (standardised curation), gnomAD/ExAC (population frequency)
• Variant calls can change over time: downgrading from P/LP to VUS requires re-contacting relatives who tested negative (they may now be at risk) and those who tested positive (management rationale changes) (sources/genetic-cmp-jcf-2018 — very high)
• Interpretation in non-European populations is particularly challenging due to underrepresentation in reference databases (sources/genetic-cmp-jcf-2018 — very high)
• See concepts/Variant-Reclassification for reclassification rates and clinical implications

Secondary and Incidental Findings

• ACMG 2016 lists 59 medically actionable genes; 30 have cardiovascular phenotypes, 16 include cardiomyopathy genes
• When P/LP variants in ACMG-listed cardiomyopathy genes are found incidentally (exome/genome sequencing for non-cardiac indication): focused cardiovascular phenotyping is recommended (sources/genetic-cmp-jcf-2018 — very high)
• Most incidental cardiomyopathy variants will remain VUS — limiting actionability
• Cascade clinical phenotyping of at-risk relatives may be considered even if the incidental proband is phenotype-negative (age-dependent penetrance)

DTC-GT vs. Clinical Genetic Testing in Cardiomyopathy

• DTC-GT panels include key cardiomyopathy genes (DCM: LMNA, TTN, MYH7, SCN5A, PLN, FLNC, RBM20, DSP, BAG3; HCM: MYBPC3, MYH7, TNNT2, TNNI3; ARVC: PKP2, DSP, DSC2, TMEM43, DSG2, JUP; storage diseases: TTR, GLA, GAA) — Table 1 of the AHA 2025 DTC-GT statement provides a comprehensive list cross-referenced against ClinGen evidence tiers (sources/consumer-genetictest-aha-2025 — high)
• DTC-GT uses SNP-chip genotyping in most cases, not full sequencing — this creates a substantially higher false-negative rate for rare pathogenic variants than clinical-grade multigene panels; a negative DTC result does NOT exclude a genetic cardiomyopathy (sources/consumer-genetictest-aha-2025 — high)
• Confirmatory CLIA-certified testing is mandatory for any actionable monogenic DTC-GT result before clinical management changes; consumers should not alter therapy based on DTC results alone (sources/consumer-genetictest-aha-2025 — high)
• VUS burden is high in DTC-GT; third-party re-interpretation services for raw DTC genetic data are unregulated and should not guide clinical decisions (sources/consumer-genetictest-aha-2025 — high)
• For comprehensive framework on DTC-GT in cardiovascular medicine, see concepts/DTC-Genetic-Testing

Special Contexts

Paediatric Considerations

• Children require specialist evaluation: syndromic and metabolic causes represent a substantially higher proportion than in adults
• Age at presentation guides differential:
  • Infancy: inborn errors of metabolism dominate (Pompe, fatty acid oxidation defects, mitochondrial); RASopathies (Noonan)
  • Childhood: neuromuscular disorders (Duchenne, Barth syndrome in boys), mitochondrial disease, Danon disease
  • Any age: same familial HCM and DCM genes as adults
• Metabolic screening (acylcarnitine profile, amino acids, urine organic acids, serum lactate) is first-line in infants before genetic sequencing
• Genetic testing in minors for adult-onset cardiomyopathy: controversial; generally deferred until clinical features become likely; requires multidisciplinary team input

Mitochondrial Disease — Special Considerations

• Standard cardiomyopathy and arrhythmia gene panels do NOT include mitochondrial genes — neither mtDNA-encoded nor nuclear-encoded mitochondrial genes are part of current cardiomyopathy panel offerings. A negative panel does not exclude a mitochondrial aetiology. (sources/mitochondrial-cv-aha-2025, rating: very high)
• WGS (or WES) is recommended as first-line for suspected mitochondrial disease, rather than targeted gene panels. (sources/mitochondrial-cv-aha-2025)
• Suspect mitochondrial disease when cardiomyopathy is accompanied by: maternal inheritance pattern; multisystemic involvement (neurological, ophthalmological, auditory, endocrine, renal); elevated serum lactate; antenatal or early-infantile presentation; diabetes + deafness; or no P/LP variant found on standard cardiomyopathy panels.
• Mitochondrial genetics has unique non-Mendelian features (concepts/Heteroplasmy) — heteroplasmy, biochemical thresholds, maternal inheritance with variable segregation, and dynamic variant levels — that require specialist genetic counselling beyond standard Mendelian disease counselling. (sources/mitochondrial-cv-aha-2025)
• HCM is the dominant cardiomyopathy phenotype in mitochondrial disease; DCM, RCM, and hypertrabeculation also occur. CVD is the leading cause of death in adults with mitochondrial disorders. (sources/mitochondrial-cv-aha-2025)
• See concepts/Mitochondrial-Cardiomyopathy for syndrome-specific clinical features and cardiac screening recommendations.

Extended Indications

Genetic Testing for Arrhythmic Disorders — AHA 2020 Recommendations

• Disease-specific gene panels for arrhythmic disorders (per HRS/EHRA 2011 + ClinGen 2019–2020 curations): (sources/genetic-test-aha-2020 — high)
  • Long-QT syndrome: KCNQ1, KCNH2, SCN5A (3 definitively causal for typical LQTS per ClinGen 2020); additionally CALM1, CALM2, CALM3, TRDN for atypical LQTS
  • Short-QT syndrome: KCNH2, KCNQ1, KCNJ2
  • Brugada syndrome: SCN5A only (ClinGen 2019 evaluated 21 candidate genes; only SCN5A has definitive evidence; results for other genes should NOT inform clinical management)
  • CPVT: RYR2, CASQ2
• Genetic testing NOT indicated for isolated type 2 or type 3 Brugada ECG patterns (these are not diagnostic for Brugada syndrome and do not constitute an independent indication for testing)
• Genetic testing NOT routinely recommended for atrial fibrillation per HRS/EHRA 2011; evolving evidence may support testing in early-onset AF or AF with cardiomyopathy gene variants
• Out-of-hospital cardiac arrest survivors: genetic testing only when specific clinical suspicion for cardiomyopathy or channelopathy; not indicated as routine workup for all survivors
• Postmortem genetic testing: collect tissue samples; select panels guided by autopsy findings and surviving family members' clinical results; cascade testing recommended if a causal variant is identified (sources/genetic-test-aha-2020 — high)

Genetic Testing for HTAD — AHA 2020 Recommendations

• ClinGen 2018 (Renard et al.): 11 genes with definitive/strong evidence for heritable thoracic aortic aneurysm and dissection (HTAD): ACTA2, COL3A1, FBN1, MYH11, SMAD3, TGFB2, TGFBR1, TGFBR2, MYLK, LOX, PRKG1 (sources/genetic-test-aha-2020 — high)
• 8 additional potentially diagnostic genes included in most commercial aortopathy panels: EFEMP2, ELN, FBN2, FLNA, NOTCH1, SLC2A10, SMAD4, SKI
• Gene identification provides actionable information: guides surgical timing thresholds, determines scope of vascular surveillance, and identifies risk of additional systemic vascular diseases
• ACTA2 pathogenic variants → elevated risk for early-onset stroke/MI from vascular occlusive lesions and moyamoya disease, beyond aortic disease alone
• 70% of HTAD families without systemic features (Marfan/Loeys-Dietz phenotype) test negative on current panels — additional undiscovered genes suspected; refer panel-negative HTAD families to research studies

Contradictions / Open Questions

• VUS dilemma in practice: Both HFSA 2018 and all subsequent guidelines agree VUS should not drive cascade genetic testing. Yet a substantial proportion of probands receive a VUS rather than P/LP classification — particularly in DCM, where most genes contribute a small fraction and novel variants are common. This leaves the majority of families with likely inherited disease unable to access gene-informed cascade testing. (sources/genetic-cmp-jcf-2018 — very high; sources/HCM-AHA-2024 — high)
• TTNtv pathogenicity uncertainty: TTNtv is found in 10–20% of DCM but also in ~1% of the general population and in athletes with physiological remodelling. Non-segregating TTNtv cases have been documented. Many commercial labs classify all TTNtv as P/LP — yet the variant may function as a risk allele requiring a "second hit" rather than a fully penetrant pathogenic variant. The clinical actionability of a TTNtv in an asymptomatic relative is not well-established. (sources/genetic-cmp-jcf-2018 — very high; sources/esc-cmp-2023 — very high)
• Diagnostic yield gap — negative result ≠ non-genetic: Genetic testing yields <100% for every phenotype. A negative result in the proband does not exclude a genetic cause; it merely means the current panel could not identify one. However, this uninformative result cannot be used for cascade testing — families are left in a state where phenotypic surveillance is required indefinitely with no genetic clarity. (sources/genetic-cmp-jcf-2018 — very high)
• Variant reclassification notification gap: Downgrading a P/LP variant to VUS has immediate clinical implications — relatives who were told they are "gene-negative" may now be at undetermined risk. No standardised infrastructure exists for systematic notification. See concepts/Variant-Reclassification. (sources/arrhythmia-genetics-mgenetik-2025 — high; sources/HCM-AHA-2024 — high)
• Non-European population underrepresentation: Most pathogenic variant repositories are derived from white/northern European cohorts. Variant interpretation in other ethnicities is substantially more difficult and more likely to yield VUS, creating health equity disparities in genetic medicine. (sources/genetic-cmp-jcf-2018 — very high)
• Mitochondrial causes missed by standard panels: All major guidelines recommend multigene panel testing as the standard of care for cardiomyopathy. However, these panels do not test mitochondrial genes. A patient with mitochondrial cardiomyopathy (e.g., MELAS-related HCM, Barth syndrome DCM) will receive a "negative" result and potentially be misclassified as gene-elusive, delaying correct diagnosis and inappropriate family counselling. No guidelines formally specify at what point a panel-negative result should prompt escalation to WGS with mitochondrial analysis. (sources/mitochondrial-cv-aha-2025 — very high)
• Gene-specific ICD thresholds vs. standard LVEF cutoff: The standard LVEF ≤35% threshold underestimates risk in high-risk genotypes (LMNA, PLN, FLNC, RBM20). Guidelines agree on the principle of gene-specific expanded thresholds, but the exact thresholds differ between ESC 2021, ESC 2022, and ESC CMP 2023, creating clinical uncertainty. (sources/genetic-cmp-jcf-2018 — very high; sources/VA-SCD-ESC-2022 — very high; sources/esc-cmp-2023 — very high)

Connections

• Related to concepts/Cascade-Family-Screening
• Related to concepts/Variant-Reclassification
• Related to concepts/Cardiogenetic-Centers
• Related to concepts/Phenotypic-Approach-to-Cardiomyopathy
• Related to entities/HCM
• Related to entities/DCM
• Related to entities/ARVC
• Related to entities/RCM
• Related to entities/LMNA
• Related to entities/TTN
• Related to entities/MYBPC3
• Related to entities/MYH7
• Related to entities/PKP2
• Related to entities/ATTR-Amyloidosis
• Related to entities/Fabry-Disease
• Related to concepts/Fabry-Cardiomyopathy
• Related to concepts/Genetic-Testing-in-AF
• Related to concepts/DTC-Genetic-Testing
• Related to concepts/Mitochondrial-Cardiomyopathy
• Related to concepts/Heteroplasmy
• Related to sources/genetic-cmp-jcf-2018
• Related to sources/esc-cmp-2023
• Related to sources/HF-AHA-2022
• Related to sources/HF-ESC-2021
• Related to sources/eoaf-jama-2021
• Related to sources/genetic-yield-jama-card-2022
• Related to sources/HCM-AHA-2024
• Related to sources/mitochondrial-cv-aha-2025
• Related to sources/consumer-genetictest-aha-2025
• Related to sources/genetic-test-aha-2020
• Related to sources/arrhythmia-genetics-mgenetik-2025
• Related to sources/VA-SCD-ESC-2022

Sources

• sources/HCM-AHA-2024
• sources/HF-AHA-2022
• sources/HF-ESC-2021
• sources/VA-SCD-ESC-2022
• sources/arrhythmia-genetics-mgenetik-2025
• sources/consumer-genetictest-aha-2025
• sources/eoaf-jama-2021
• sources/esc-cmp-2023
• sources/genetic-cmp-jcf-2018
• sources/genetic-test-aha-2020
• sources/genetic-yield-jama-card-2022
• sources/mitochondrial-cv-aha-2025