Why
Genotype
Changes SCD / ICDRisk can be out of proportion to EF — LMNA·FLNC·PLN·DSP·RBM20 may support considering an ICD at higher EF when validated gene-specific risk factors or scores apply; genotype alone is not the indication.
Screens the familyA pathogenic variant turns the kindred into a cascade-screening program.
Some are actionableStorage mimics (Fabry · Pompe · amyloid) are treatable → Infiltrative card.
Proband firstFind a P/LP variant in an affected person before testing relatives; a VUS doesn't drive cascade.
01
Structural families
where the gene sits
- Sarcomeric MYH7·MYBPC3·TNNT2·TNNI3·TPM1·ACTC1 → HCM.
- Desmosomal PKP2·DSG2·DSC2·DSP·JUP → ARVC/ACM.
- Cytoskeleton / Z-disc / envelope TTN·LMNA·FLNC·DES·BAG3·PLN·RBM20·SCN5A → DCM/ACM (P.3).
- Trabecular hypertrabeculation → LVNC.
- Storage GLA·GAA·PRKAG2·LAMP2·TTR → Infiltrative.
Overlap is the rule
- One gene → several phenotypes across a family (DSP: DCM · ACM · "myocarditis").
- "Arrhythmogenic CM" spans desmosomal and non-desmosomal genes.
- A normal echo does not exclude a high-risk genotype — conduction / VA / LGE can come first.
02
Inheritance
who is at risk
- Autosomal dominant most CM genes — 50% transmission.
- X-linked Fabry (GLA), Danon (LAMP2) — males severe.
- Autosomal recessive mostly storage/metabolic (Pompe).
- Mitochondrial maternal; multisystem (deafness, lactic acidosis).
- De novo possible — severe pediatric disease.
Penetrance & expressivity
- Age-dependent & incomplete penetrance — carriers phenotype over decades.
- Variable expressivity — same variant, different severity.
- Skipped generations expected; modifiers: sex, 2nd variants, exercise.
03
When & how to test
ACMG · HFSA · 2023 ESC
- Indication offer counseling and phenotype-directed testing when a result can inform diagnosis, prognosis, treatment or family screening.
- Method phenotype-directed multigene panel in the proband + counseling.
- 2023 ESC first full-spectrum CM guideline.
ACMG 5-tier
- P / LP → actionable; drives cascade + management.
- VUS → not actionable; don't cascade; re-review over time.
- Segregation + deep phenotyping aid reclassification.
▦
Gene → phenotype map
⚡ = high-risk arrhythmic · overlap common
| Family | Representative genes | Dominant phenotype | Card |
|---|
| Sarcomeric | MYBPC3 · MYH7 · TNNT2 · TNNI3 · TPM1 | HCM (LVH, outflow obstruction) | HCM → |
| Desmosomal | PKP2 · DSG2 · DSC2 · JUP · DSP⚡ | ARVC / arrhythmogenic | ARVC → |
| DCM / ACM | TTN · LMNA⚡ · FLNC⚡ · PLN⚡ · RBM20⚡ · DES · BAG3 · SCN5A | Dilated / arrhythmogenic / non-dilated LV | P.3 |
| Trabecular | mixed (sarcomeric · TTN · syndromic) | LV non-compaction | LVNC → |
| Storage | GLA · GAA · PRKAG2 · LAMP2 · TTR | HCM-mimic / restrictive (treatable) | Infilt → |
| Syndromic | RASopathy (Noonan: PTPN11) · mitochondrial | syndromic HCM / multisystem | — |
TTN truncating = commonest genetic DCM (~25% familial); the ⚡ genes share a theme — arrhythmia/SCD precedes or exceeds systolic dysfunction, so EF-based ICD rules under-protect them.
◎
Phenocopies — when LVH isn't sarcomeric HCM
treatable mimics → don't miss them
| Condition (gene) | Red flag beyond LVH | Confirm |
|---|
| Fabry (GLA) | low native T1, neuropathic pain, cornea verticillata, proteinuria, short PR | α-Gal A (♂) / GLA + lyso-Gb3 (♀) |
| Amyloid (TTR) | low voltage, apical sparing, bilateral carpal tunnel, neuropathy | ⁹⁹ᵐTc-PYP + serum free light chains and serum/urine immunofixation (exclude AL) |
| Danon (LAMP2) | X-linked, skeletal myopathy, intellectual disability, retinopathy, WPW | LAMP2 gene; very high LV mass |
| PRKAG2 | WPW pre-excitation + progressive conduction block | PRKAG2 gene; glycogen vacuoles |
| Pompe (GAA) | infantile HCM + hypotonia; late-onset limb-girdle myopathy | GAA enzyme (dried blood spot) + gene |
| Friedreich ataxia (FXN) | ataxia, diabetes, scoliosis | FXN repeat expansion |
| Noonan / RASopathy | dysmorphism, pulmonary stenosis, short stature | RAS-pathway panel (PTPN11 …) |
⌕
Genetic testing — practical points
panel · proband · reanalysis · counseling
- First-line phenotype-directed multigene panel; reserve broad WES/WGS for atypical / syndromic disease.
- No proband? test the most-affected living relative.
- Yield highest in HCM / ARVC; lower in sporadic DCM (TTNtv aside).
- Reanalyze unsolved cases periodically — new genes + variant reclassification.
- Secondary findings report actionable ACMG genes per policy + consent.
- VUS don't act, don't cascade; pursue segregation + functional data.
- Special assays CNV + repeat expansion (e.g., FXN) when phenotype fits.
- Turnaround weeks; bracket with pre/post-test counseling.
- GINA (US) review jurisdiction-specific insurance and employment implications during genetic counseling before testing.
- Document the variant + pedigree in the chart for future relatives.
01
Build the pedigree
3–4 generations
- CM, HF, transplant, pacemaker/ICD, and SCD with age at each.
- SCD surrogates: unexplained drowning, single-car MVA, "epilepsy", SIDS.
- Founder variants by ancestry (Dutch PLN R14del); consanguinity.
- Extracardiac clues: deafness, myopathy/↑CK, renal, neuropathy, ID.
Red flags in the tree
- SCD < 50 yr, multiple affected, early pacemaker/ICD.
- Maternal-line clustering → mitochondrial.
- Skipped generations expected (incomplete penetrance).
02
Proband → cascade
variant first, then family
1 · Proband Test the affected person; seek a P/LP variant.
2 · Cascade P/LP found → predictive testing of first-degree relatives, outward.
3 · Variant− Phenotype-negative relatives negative for a confidently causal family P/LP variant can usually leave surveillance.
No variant / VUS Use clinical family screening instead.
Caveats
- Pre/post-test genetic counseling is standard of care.
- Mind insurance / psychosocial; test minors when actionable.
03
The G+ / P− relative
carrier, not yet affected
- Genotype-positive, phenotype-negative → surveillance, not discharge.
- Phenotype emerges over time — penetrance is age-dependent.
- Baseline ECG + echo; add CMR / Holter by gene.
Counsel on
- Reproductive options (prenatal / preimplantation).
- Exercise — individualize by genotype, phenotype and sport with an expert (P.3).
- Lifestyle: BP, alcohol, stimulant avoidance.
⏱
Clinical surveillance cadence
ECG + echo baseline in all relatives
| Group | Tests | Interval | Escalate when |
|---|
| Child / adolescent | ECG + echo (± exercise test) | q1–2 yr | symptoms / ECG-echo change → CMR |
| Adult relative | ECG + echo; CMR & Holter by phenotype | q2–3 yr | LGE, NSVT, falling LVEF → EP |
| Arrhythmogenic genotype | ECG + echo + Holter + CMR | q1–2 yr, lifelong | conduction disease / VA → ICD (P.3) |
| Variant− | — | discharge | only if a definite family P/LP exists |
⚑
Special situations
pregnancy · sport · pediatrics · VUS
- Pregnancy pre-conception risk assessment + antenatal surveillance; LMNA / arrhythmogenic + low LVEF = higher peripartum risk.
- Competitive sport genotype- & phenotype-informed pre-participation; individualize by genotype, phenotype and sport with an expert.
- Pediatric onset often severe / de-novo — co-manage with pediatric cardiology + genetics.
- VUS over time re-contact the family when reclassified — can open or close cascade testing.
◷
Screening relatives by phenotype
when to start · what · how often
| Proband phenotype | Start screening | Tests | Then |
|---|
| HCM | At family diagnosis for genotype-positive or early-onset families, otherwise no later than puberty | ECG + echo | Children q1–2 yr if high-risk family, otherwise q2–3 yr. Adults q3–5 yr |
| DCM | childhood | ECG + echo (± CMR) | q1–3 yr; sooner for arrhythmogenic genes |
| ARVC / ACM | ~10–12 yr | ECG + echo + Holter + CMR | q1–2 yr; restrict sport |
| LVNC | childhood | ECG + echo | q2–3 yr; disease vs trait |
| Variant− relative | — | — | release only if phenotype-negative and the familial P/LP remains causal |
☎
Predictive testing & counseling
process · children · reproductive
- Predictive testing only after a P/LP variant is confirmed in an affected proband.
- Offer to first-degree relatives; cascade outward as each tests positive.
- Children test when it changes surveillance / management (true for most CM genes).
- Reproductive PGT-M, prenatal diagnosis, donor gametes — refer to reproductive genetics.
- Psychosocial family communication + the "right not to know".
- Insurance discuss before testing (GINA limits; life/disability not covered).
- Re-contact families when a VUS is reclassified.
- Team coordinate via a genetic counselor / inherited-cardiac-conditions clinic.
⚡
The red-flag DCM / ACM genes
arrhythmia out of proportion to EF
| Gene | Inherit | Phenotype & ECG/CMR clue | Risk & management pearl |
|---|
| LMNA⚡ | AD | Conduction disease first (PR↑→AV block, AF) then VA; septal/mid-wall LGE | Pace for block does not protect from VT → ICD; use the LMNA score ↓ |
| FLNC tv⚡ | AD | Dilated/arrhythmogenic overlap; ring-like subepicardial LGE | Events occur above LVEF 35% → integrate LGE, arrhythmia and gene-specific guidance for ICD decisions |
| PLN R14del⚡ | AD | Low QRS voltage (~46%); posterolateral scar/fat; DCM-ARVC overlap | Appropriate shocks 47% vs 10%; transplant 18% vs 2% vs R14del− |
| DSP⚡ | AD | LV-predominant, fibrotic/inflammatory; "hot phases" mimic myocarditis; lateral LGE | VA can precede EF drop; recurrent injury should prompt genetic evaluation, while excluding other myocarditis causes |
| RBM20⚡ | AD | Aggressive, young; disturbed Ca²⁺ handling | Sustained VA 44% vs 5% (TTN) at similar EF; youngest transplant |
| TTN tv | AD | Commonest genetic DCM (~25% familial); distal A-band; AF common | Often reverse-remodels with GDMT. Apply phenotype-based ICD assessment, including scar and arrhythmia |
| TMEM43 | AD | ACM (S358L founder) | High male SCD — early ICD in males |
| SCN5A | AD | DCM + conduction disease / arrhythmia (Brugada · LQT3 overlap) | check ECG phenotype; mind Na-channel / QT-offenders |
| DES (desmin) | AD | Myofibrillar myopathy + DCM/restrictive + conduction block | skeletal myopathy / ↑CK; early pacing need |
| BAG3 | AD | Young, progressive familial DCM ± peripheral myopathy | include on the DCM panel |
| JPH2 · ACTN2 · NEXN | AD | HCM / DCM / LVNC overlap (lower frequency) | panel completeness; phenotype-guided |
A
LMNA risk score
Wahbi · Circ 2019
- Male sex
- Non-missense variant
- ≥ 1° AV block
- NSVT
- LVEF (lower = worse)
≥7%5-yr LTVTA: original study cutpoint, not an automatic ICD rule
0.80C-index
B
ICD decision
gene + validated modifiers
- Higher-risk genes LMNA·FLNC·PLN·DSP·RBM20 can support considering ICD at higher EF only in gene-specific context with validated modifiers/scores; not from genotype alone.
- Modifiers LGE extent, NSVT, syncope, family SCD.
- Secondary prev. aborted SCD / sustained VA → ICD regardless of EF.
- TTN assess EF, scar and arrhythmia under the DCM pathway.
C
Directed care
beyond the device
- GDMT full HF therapy; TTN reverse-remodels.
- Exercise avoid high-intensity endurance exercise in established ARVC, especially PKP2. Other genotypes need expert shared decisions.
- Advanced HF LMNA·FLNC·RBM20·PLN progressive → early transplant/MCS (when symptoms or objective deterioration warrant).
- Family cascade-screen every new proband (P.2).
⚙
Rhythm & device pearls
genotype-directed
- Device choice high-risk gene + indication → ICD (CRT-D if CRT-indicated); avoid pacemaker-only when VT risk is high (LMNA).
- VT ablation adjunct for recurrent VT (esp. ARVC/DSP scar) — not a substitute for an ICD.
- Anticoagulation AF or LV thrombus; LMNA atrial standstill carries embolic risk even in sinus rhythm.
- AF / atrial myopathy common in LMNA·PLN — rate/rhythm control + stroke prophylaxis.
- GDMT full HF therapy for all; watch for progression to advanced HF.
- Re-image serial CMR/LGE — scar extent tracks arrhythmic risk.
- Wearable defibrillator bridge a newly-diagnosed high-risk patient awaiting risk stratification.
- CRT per LBBB / EF criteria — choose CRT-D over CRT-P in high-risk genes.
- Transplant / LVAD LMNA·FLNC·RBM20·PLN may progress to advanced HF — refer by trajectory and standard eligibility.
- Drugs avoid QT-prolongers in SCN5A-LQT3 overlap; phenotype-guided β-blockade.
KEY
In genetic DCM/ACM, EF alone underestimates SCD risk — highest VA/SCD & transplant in LMNA & PLN, youngest transplant in RBM20. Use the genotype, the LMNA score, and LGE/NSVT for the ICD — and screen the family. A TTN variant does not establish low individual arrhythmic risk.