MYH7
35–40% of familial HCM | HCM
Hypertrophic Cardiomyopathy | Sarcomere
Thick filament (β-MHC) | AD
Autosomal Dominant | Predominantly Missense (>95%) | Dominant Negative | - Accounts for 35–40% of familial HCM; alongside MYBPC3 the most commonly identified causal gene[2]
- Predominantly missense variants (>95%); truncating MYH7 variants are rare and when present more commonly cause DCM rather than HCM[1][2]
- Mechanism: mutant β-myosin heavy chain incorporates into thick filaments as a "poison peptide", actively disrupting cross-bridge cycling via dominant negative effect, reducing total functional myosin disproportionately[9]
- Earlier onset, greater hypertrophy, and higher SCD risk compared to MYBPC3-HCM; higher penetrance overall[9]
- Cysteine substitutions in the myosin head domain (e.g., p.Arg403Gln) are among the most severe and penetrant; associated with early-onset presentation and high SCD risk[2][9]
|
MYBPC3
35–40% of familial HCM | HCM
Hypertrophic Cardiomyopathy | Sarcomere
Thick filament (cMyBP-C) | AD
Autosomal Dominant | Truncating & Missense (~70:30) | Haploinsufficiency | - Alongside MYH7, the most commonly identified HCM gene (~35–40% of familial cases)[2]
- ~70% of pathogenic variants are truncating (frameshift, nonsense, splice-site) → NMD of mutant transcript → haploinsufficiency; ~30% are missense variants[1][2]
- Mechanism: reduced cMyBP-C protein levels alter sarcomeric cross-bridge kinetics and Ca²⁺ sensitivity, impairing both contraction and relaxation[9]
- Later onset and lower penetrance than MYH7; penetrance strongly age-related (increases each decade), many carriers are unaffected in the 3rd–4th decade[9]
- South Asian founder variant c.2373insG (p.Gln791fs) is among the most prevalent HCM variants worldwide; homozygous carriers develop severe childhood-onset HCM[2]
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TNNT2
~5% of familial HCM | HCM
Hypertrophic Cardiomyopathy | Sarcomere
Thin filament (troponin T) | AD
Autosomal Dominant | Predominantly Missense | Dominant Negative | - Accounts for ~5% of familial HCM[2]
- Predominantly missense variants disrupting troponin T interaction with the thin filament regulatory complex[2]
- Mechanism: increased myofilament Ca²⁺ sensitivity and impaired diastolic relaxation; dominant negative effect reduces total thin filament regulation disproportionately[9]
- Disproportionately high SCD risk relative to degree of hypertrophy, some carriers die with near-normal or only mildly increased wall thickness[9]
- Standard echocardiographic risk tools may underestimate SCD risk; genetic diagnosis is critical for appropriate surveillance intensity[9]
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TNNI3
~5% of familial HCM | HCM
Hypertrophic Cardiomyopathy | Sarcomere
Thin filament (troponin I) | AD
Autosomal Dominant | Predominantly Missense | Dominant Negative | - Accounts for ~5% of familial HCM[2]
- Predominantly missense variants (e.g., p.Arg145Gly, p.Arg162Gln) disrupting the inhibitory troponin I–actin interaction[2]
- Mechanism: increased myofilament Ca²⁺ sensitivity → sustained systolic activation, impaired relaxation[9]
- Associated with apical HCM variant in some kindreds[9]
- Important allelic distinction: biallelic TNNI3 variants (different mechanism, gene dosage) cause restrictive cardiomyopathy in childhood, demonstrates how variant zygosity dictates phenotypic outcome within the same gene[9]
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TPM1
~2% of familial HCM | HCM
Hypertrophic Cardiomyopathy | Sarcomere
Thin filament (α-tropomyosin) | AD
Autosomal Dominant | Predominantly Missense | Dominant Negative | - ~2% of familial HCM[2]
- Predominantly missense variants in the α-tropomyosin coiled-coil domain[2]
- Mechanism: shifts the thin filament toward the "on" state, increasing Ca²⁺ sensitivity and resting force generation[9]
- The same gene causes DCM when different variants have the opposite functional effect (reduced Ca²⁺ sensitivity), demonstrates how allelic heterogeneity determines cardiomyopathy subtype[1][9]
- Illustrates that phenotypic direction of a cardiomyopathy can be determined at the level of the individual variant within a single gene[9]
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TTN
~25% familial DCM; ~18% sporadic DCM | DCM
Dilated Cardiomyopathy | Sarcomere
Elastic filament (titin) | AD
Autosomal Dominant | Truncating only (TTNtv) | Haploinsufficiency | - The most common genetic cause of DCM (~25% of familial, ~18% of sporadic cases)[3]
- Exclusively truncating variants (TTNtv: frameshift, nonsense, splice-site) in constitutively expressed A-band exons (PSI ≥0.9) are established as pathogenic; TTN missense variants are not validated disease-causing[3]
- Mechanism: haploinsufficiency reduces titin-based passive tension and impairs sarcomere assembly and mechano-sensing[3]
- Incomplete penetrance (~40% in males, ~22% in females); environmental second-hits (alcohol, peripartum state, viral myocarditis) likely required for disease expression[3][9]
- Strong association with peripartum cardiomyopathy, TTNtv carriers have lower rates of LV recovery following PPCM compared to non-carriers[3][9]
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LMNA
~6% of DCM | DCM
Dilated Cardiomyopathy | Nuclear Envelope
Nuclear lamina | AD
Autosomal Dominant | Truncating & Missense (~50:50) | Haploinsufficiency | - ~6% of DCM; a high-risk gene requiring proactive arrhythmia management[10]
- Approximately equal proportions of truncating and missense variants, both can cause severe disease; non-missense variant type is an independent risk factor for worse arrhythmic outcomes[9][10]
- Conduction disease (AV block, bundle branch block, AF) typically precedes systolic impairment by years; initial presentation may mimic isolated conduction system disease[10]
- Ventricular arrhythmias and SCD risk are high even at preserved LVEF, ICD recommended at lower thresholds than non-LMNA DCM; the LMNA risk score (NSVT, LVEF, male sex, non-missense variant) guides decisions[9]
- Early cardiac transplant listing is often appropriate given propensity for rapid, refractory disease progression[9][10]
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PLN
Dutch/N. European founder variant | DCM
Dilated Cardiomyopathy | Ca²⁺ Handling
SR Ca²⁺ pump (SERCA2a) | AD
Autosomal Dominant | Missense / Small Deletion (p.Arg14del dominant) | Dominant Negative | - p.Arg14del is the dominant pathogenic variant; a founder variant prevalent in Dutch and Northern European populations[11]
- Functionally a dominant negative "super-inhibitor": p.Arg14del PLN chronically impairs SERCA2a Ca²⁺ reuptake into the SR beyond normal inhibition[11]
- Mechanism: diastolic Ca²⁺ overload → triggered ventricular arrhythmias and progressive cardiomyocyte dysfunction, leading to DCM[11]
- Ventricular arrhythmias (VT/VF) occur at relatively preserved LVEF, early ICD is strongly recommended even before significant LV dysfunction[11][9]
- High cardiac transplantation rate; prognosis without aggressive early management is poor[11]
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RBM20
~2% of DCM | DCM
Dilated Cardiomyopathy | Sarcomere
Titin splicing (RBM20) | AD
Autosomal Dominant | Predominantly Missense (RSRSP hotspot) | Loss of Function | - ~2% of DCM; pathogenic variants are concentrated in the arginine-serine-rich RSRSP motif of the RNA-binding domain[10]
- Predominantly missense variants within this hotspot; truncating variants outside this region may have milder or absent pathogenicity[10]
- Mechanism: loss of titin mRNA splicing regulation → giant non-compliant titin isoforms → abnormal sarcomere mechanics and impaired Ca²⁺ handling[10]
- Aggressive phenotype: severe early-onset DCM with one of the highest VT/VF burdens of any DCM gene, ICD indication is strong even at modest LV impairment[9][10]
- Cardiac transplantation often required in the 3rd–4th decade; RSRSP hotspot variants carry particularly poor prognosis[10]
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FLNC
~4% of DCM | DCM
Dilated Cardiomyopathy | Cytoskeleton
Z-disc / cytoskeletal linker | AD
Autosomal Dominant | Predominantly Truncating | Haploinsufficiency | - ~4% of DCM; truncating FLNC variants specifically cause DCM (missense FLNC variants more commonly associate with HCM or myofibrillar myopathy)[1][10]
- Predominantly truncating variants (frameshift, nonsense) → haploinsufficiency of filamin C → impaired cytoskeletal linkage and mechanical resilience[10]
- High arrhythmia burden disproportionate to the degree of LV dysfunction; NSVT and sustained VT are common early in the disease course[9][10]
- Cardiac biopsy shows protein aggregates (desmin, αB-crystallin), a distinguishing feature from sarcomeric DCM that may aid diagnosis[10]
- ICD strongly indicated even at modest LV dysfunction; assess for skeletal muscle involvement (myofibrillar myopathy)[9]
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SCN5A
~2–3% of DCM | DCM
DCM with Conduction Disease | Ion Channel
Na⁺ channel (Nav1.5) | AD
Autosomal Dominant | Truncating & Missense (LoF) | Loss of Function | - ~2–3% of DCM; Nav1.5 loss-of-function causes a form of cardiomyopathy with prominent conduction disease[10]
- Mix of truncating and missense LoF variants; both reduce peak INa in working cardiomyocytes[10]
- Conduction disease (AV block, sinus node dysfunction, bundle branch block) commonly precedes LV systolic impairment, initial presentation may be indistinguishable from isolated conduction system disease[9][10]
- Overlap with Brugada syndrome: some SCN5A LoF carriers manifest a type 1 Brugada ECG pattern on sodium channel blockade or fever[4][12]
- Pacemaker frequently required in addition to ICD; mechanistically distinct from sarcomeric DCM and may represent a primary electrical cardiomyopathy[9]
|
PKP2
~40–45% of ARVC | ARVC
ARVC | Desmosome
Desmosomal plaque (PKP2) | AD
Autosomal Dominant | Truncating (predominant) & Missense | Haploinsufficiency | - The most common ARVC gene, accounting for ~40–45% of cases[6]
- Predominantly truncating variants (~60%); missense variants (~40%) also pathogenic; truncating variants generally associate with higher penetrance[1][6]
- Mechanism: plakophilin-2 haploinsufficiency disrupts desmosomal integrity → cardiomyocyte detachment under mechanical stress → fibrofatty replacement predominantly in the RV free wall[6]
- Exercise substantially accelerates disease progression, and restriction from competitive and endurance sport is strongly advised from the time of genetic diagnosis, though the intensity/type of permitted activity may be individualized with specialist input[6]
- Penetrance is incomplete and sex-dependent (higher in males); index cases typically present with VT or aborted cardiac arrest in the 2nd–4th decade[6]
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DSP
~10–15% of ARVC/ACM | ARVC
Arrhythmogenic Cardiomyopathy (ACM) | Desmosome
Desmoplakin (DSP) | AD
Autosomal Dominant | Predominantly Truncating | Haploinsufficiency | - Accounts for ~10–15% of ARVC/ACM; causes a predominantly left-sided or biventricular phenotype ("DSP cardiomyopathy") rather than classic right-dominant ARVC[6]
- Predominantly truncating variants (frameshift, nonsense, splice-site); missense variants also described in the N-terminal plakin domain[1][6]
- Epicardial LGE on CMR (particularly in the LV lateral wall) is a hallmark finding; higher SCD risk than PKP2-ARVC[6]
- Biallelic DSP variants cause Carvajal syndrome: ACM + woolly hair + palmoplantar keratoderma (complete penetrance in biallelic carriers)[6]
- Exercise restriction and ICD indications mirror PKP2-ARVC; the left-dominant phenotype may cause diagnostic delay if ARVC is not initially considered[6]
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DSG2
~5–10% of ARVC | ARVC
ARVC | Desmosome
Desmosomal cadherin (DSG2) | AD
Autosomal Dominant | Missense & Truncating | Loss of Function | - ~5–10% of ARVC; desmoglein-2 loss-of-function impairs desmosomal cohesion between adjacent cardiomyocytes[6]
- Mix of missense and truncating variants; both reduce desmoglein-2 adhesive function via different mechanisms[1][6]
- Can present with mixed right and left ventricular involvement; phenotype may overlap with DCM or ACM[6]
- Important diagnostic pitfall: some DSG2 carriers initially meet HCM criteria before evolving to an ARVC/ACM phenotype, longitudinal surveillance and genetic diagnosis are essential in atypical cardiomyopathy presentations[6]
- Compound heterozygous DSG2 variants (two different variants on separate alleles) may produce more severe disease[6]
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JUP
Rare; Greek island founder variant | ARVC
Naxos Disease (AR-ACM) | Desmosome
Armadillo protein (JUP) | AR
Autosomal Recessive | Truncating (biallelic) | Loss of Function | - Rare; requires biallelic truncating variants, homozygous c.2157del2 is the Greek island founder variant[6]
- Clinical triad: arrhythmogenic cardiomyopathy + woolly hair + palmoplantar keratoderma; full penetrance in biallelic carriers[6]
- Mechanism: complete JUP loss disrupts both desmosomal adhesion and Wnt/β-catenin signalling, promoting fibrofatty myocardial replacement[6]
- Heterozygous carriers are largely clinically unaffected, demonstrating that full JUP loss (not haploinsufficiency) is required for disease, contrasting with most desmosomal AD variants[6]
- Exemplifies how the same gene causes fundamentally different phenotypes based on zygosity: biallelic → severe syndromic disease; monoallelic → no significant disease[6]
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KCNQ1
~30–35% of LQTS | LQT
Long QT Syndrome Type 1 | Ion Channel
K⁺ channel, IKs (KCNQ1) | AD
Autosomal Dominant | Missense (predominant) & Truncating | Loss of Function | - Most common LQTS gene (~30–35% of cases); reduces IKs (slow delayed rectifier) current duration[4]
- Predominantly missense variants (~70%); truncating variants (~30%) cause haploinsufficiency; missense variants with dominant negative effect on the tetrameric IKs channel tend to cause more severe phenotype[4][5]
- Classic trigger: exercise and swimming (physiological IKs augmentation during adrenergic stimulation is absent), events are largely preventable with beta-blockers; strongest drug response of any LQTS subtype[4][5]
- ECG: characteristic broad-based or monophasic T-wave; QTc may appear near-normal at rest in some carriers[4]
- Biallelic KCNQ1 variants → Jervell and Lange-Nielsen syndrome: congenital sensorineural deafness + severe LQT1 with high arrhythmia risk, requiring aggressive management[4][5]
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KCNH2
~25–30% of LQTS | LQT
Long QT Syndrome Type 2 | Ion Channel
K⁺ channel, IKr (hERG) | AD
Autosomal Dominant | Missense (predominant) & Truncating | Dominant Negative | - Second most common LQTS gene (~25–30%); reduces IKr (rapid delayed rectifier) current duration[4]
- Predominantly missense variants (~80%); many cause protein trafficking defects, mutant channels are retained in the ER reducing surface IKr; dominant negative mechanism is common; truncating variants (~20%) cause haploinsufficiency[4]
- Classic triggers: sudden auditory stimuli (alarm clocks, phone), emotional stress, and the postpartum period, events occur in these specific contexts[4][5]
- ECG: notched, bifid, or low-amplitude T-waves; QTc may be normal or borderline at rest especially in younger females[4]
- Strict avoidance of all QT-prolonging drugs is paramount; moderate beta-blocker response; left cardiac sympathetic denervation or ICD for high-risk or refractory cases[5]
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SCN5A
~5–10% of LQTS | LQT
Long QT Syndrome Type 3 | Ion Channel
Na⁺ channel (Nav1.5) | AD
Autosomal Dominant | Predominantly Missense (GoF) | Gain of Function | - ~5–10% of LQTS; gain-of-function Nav1.5 variants (predominantly missense) prevent complete channel inactivation after depolarisation[4]
- Persistent late INa prolongs the plateau phase (phase 2) of the action potential, causing marked QTc prolongation particularly at slow heart rates[4]
- Triggers: rest and sleep; nocturnal events are characteristic, contrasting with LQT1 (exercise) and LQT2 (auditory/emotion)[4][5]
- Beta-blockers less effective and can worsen bradycardia-related risk; late sodium current blockers (mexiletine, flecainide) shorten QTc and are key adjunctive therapy[5]
- Note: LoF variants in the same SCN5A gene cause Brugada syndrome, opposite mechanism, opposite ECG, opposite trigger; illustrates importance of functional variant classification[4][12]
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KCNJ2
Rare; ~10% of unexplained LQTS | LQT
Andersen-Tawil Syndrome (LQT7) | Ion Channel
K⁺ channel, IK1 (Kir2.1) | AD
Autosomal Dominant | Predominantly Missense | Loss of Function | - Rare; predominantly missense variants causing loss-of-function of IK1 (inward rectifier Kir2.1)[4]
- Clinical triad: QT prolongation + periodic paralysis (hypokalaemic or normokalaemic) + dysmorphic features (micrognathia, clinodactyly, hypertelorism)[4]
- Characteristic bidirectional VT on Holter monitoring closely resembles CPVT; triggered by adrenergic stimulation and hypokalaemia[4][5]
- QTc prolongation is often modest relative to arrhythmia risk, the ECG alone significantly underestimates risk; standard LQTS risk stratification tools may not apply[4]
- Recognition requires awareness of the full triad; the periodic paralysis or dysmorphic features may be the presenting complaint rather than arrhythmia[4]
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SCN5A
~20–30% of Brugada syndrome (lower in Asian populations) | BrS
Brugada Syndrome | Ion Channel
Na⁺ channel (Nav1.5) | AD
Autosomal Dominant | Truncating & Missense (LoF) | Loss of Function | - ~15–25% of Brugada syndrome; Nav1.5 LoF is the only established monogenic cause[12]
- Mix of truncating and missense variants, both reducing peak INa; functional characterisation often required to confirm pathogenicity for individual missense variants[1][12]
- Mechanism: reduced INa in RV epicardium unmasks Ito-driven action potential notch → heterogeneous repolarisation → type 1 Brugada ECG pattern (coved ST elevation ≥2 mm in ≥2 right precordial leads)[12]
- Male predominance (8:1), testosterone amplifies Ito; fever directly suppresses Nav1.5 → fever-triggered VF is a classic presentation; nocturnal events are common[12][5]
- Spontaneous type-1 pattern carries higher risk than drug-induced; quinidine (Ito blocker) suppresses VF episodes; ICD for survivors of cardiac arrest or spontaneous type-1 pattern with documented arrhythmia[12][5]
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RYR2
~55–65% of CPVT | CPVT
CPVT Type 1 | Ca²⁺ Handling
SR Ca²⁺ release (RyR2) | AD
Autosomal Dominant | Predominantly Missense (GoF) | Gain of Function | - Most common CPVT gene (~55–65%); predominantly missense gain-of-function variants[13]
- Variants are clustered in four hotspot domains of RyR2 corresponding to inter-domain interaction surfaces (N-terminal, central, FKBP12.6-binding, and C-terminal)[13]
- Mechanism: under adrenergic stimulation, GoF RyR2 opens at abnormally low luminal SR Ca²⁺ → spontaneous Ca²⁺ sparks → delayed afterdepolarisations (DADs) → triggered bidirectional VT[13]
- Bidirectional VT on exercise testing is highly characteristic of CPVT; complete suppression of VT during exercise testing is the explicit treatment target[5][13]
- Beta-blockers first-line (nadolol > propranolol; avoid metoprolol); flecainide as adjunctive RyR2 stabiliser; ICD after aborted cardiac arrest or breakthrough arrhythmia on maximal therapy[5]
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CASQ2
~3–5% of CPVT | CPVT
CPVT Type 2 | Ca²⁺ Handling
SR Ca²⁺ buffer (calsequestrin) | AR
Autosomal Recessive | Missense & Truncating (biallelic) | Loss of Function | - ~3–5% of CPVT; autosomal recessive, biallelic variants (homozygous or compound heterozygous) are required[13]
- Mix of missense and truncating variants causing calsequestrin-2 loss-of-function or absent protein[13]
- Mechanism: CASQ2 loss impairs luminal SR Ca²⁺ buffering → RyR2 activates at lower luminal Ca²⁺ thresholds, even at lower adrenergic stimulation levels → more sensitive triggered arrhythmia[13]
- Earlier onset and often more severe than CPVT1; heterozygous carriers may have subclinical arrhythmia susceptibility on maximal exercise testing[5][13]
- Management mirrors CPVT1; outcomes more guarded and combination therapy (nadolol + flecainide) often required from the outset[5]
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LDLR
~60–80% of FH; 1 in 250 (heterozygous) | FH
Familial Hypercholesterolaemia | Lipid Metabolism
LDL receptor | AD
Autosomal Dominant | Missense, Truncating & CNV | Loss of Function | - Most common FH gene (60–80% of cases); heterozygous FH affects ~1 in 250, one of the most prevalent monogenic conditions in any population[7]
- Over 1,700 pathogenic variants: missense (~35%), null/truncating (~45%), and copy number variants/large deletions (~15%); variant class influences severity, null variants cause greater LDL elevation than partial LoF missense variants[7]
- Mechanism: impaired hepatic LDL receptor function → reduced LDL-C clearance from birth[7]
- Homozygous FH (LDL >13 mmol/L): accelerated ASCVD in childhood, aortic root stenosis and MI in the 2nd decade without aggressive treatment; requires lipoprotein apheresis ± lomitapide or evinacumab[7]
- Standard of care: high-intensity statin + ezetimibe + PCSK9 inhibitor (evolocumab/alirocumab) from diagnosis; early treatment substantially reduces lifetime ASCVD risk[7]
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APOB
~5% of FH | FH
Familial Defective ApoB | Lipid Metabolism
ApoB-100 (LDLR ligand) | AD
Autosomal Dominant | Predominantly Missense (p.Arg3527Gln dominant) | Loss of Function | - ~5% of FH (familial defective ApoB); predominantly missense variants[7]
- p.Arg3527Gln (mature protein: p.Arg3500Gln) is the dominant pathogenic variant worldwide and is one of the most common single FH-causing variants globally[7]
- Mechanism: ApoB-100 is the LDLR ligand; this missense reduces receptor binding affinity ~20-fold, impairing LDL-C clearance despite a normal LDL receptor[7]
- Phenotype generally milder than LDLR-FH: LDL typically 5–8 mmol/L, tendon xanthomata less prevalent, ASCVD risk somewhat lower for equivalent LDL levels[7]
- Good statin response (LDLR is intact and upregulated by statins); PCSK9 inhibitors are effective; frequently underdiagnosed as polygenic hypercholesterolaemia[7]
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PCSK9
~3–5% of FH | FH
Familial Hypercholesterolaemia | Lipid Metabolism
LDLR degradation (PCSK9) | AD
Autosomal Dominant | Predominantly Missense (GoF) | Gain of Function | - ~3–5% of FH; predominantly missense gain-of-function variants (e.g., p.Asp374Tyr, p.Ser127Arg)[7]
- GoF PCSK9 promotes accelerated post-endocytic LDLR degradation → reduced hepatic LDL-C clearance; p.Asp374Tyr is among the most severe GoF variants[7]
- Rare homozygous GoF PCSK9 variants cause a severe FH phenotype resembling homozygous LDLR-FH[7]
- Naturally occurring LoF PCSK9 variants (p.Tyr142X, p.Leu253Phe) confer lifelong protection against ASCVD, directly informing development of PCSK9 inhibitors (evolocumab, alirocumab), one of the most successful genetics-to-therapeutics translations[7]
- PCSK9 inhibitors are highly effective in PCSK9 GoF-FH since the elevated PCSK9 protein is the direct therapeutic target[7]
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FBN1
~75% of Marfan syndrome | Aorta
Marfan Syndrome | ECM / Matrix
Fibrillin-1 microfibril | AD
Autosomal Dominant | Missense (predominant) & Truncating | Dominant Negative | - ~75% of Marfan syndrome; over 3,000 pathogenic variants, one of the highest variant counts of any ICC gene[8]
- Predominantly missense variants (~65%), particularly cysteine substitutions in EGF-like Ca²⁺-binding domains, these produce dominant negative fibrillin-1 microfibrils that disrupt extracellular matrix and dysregulate TGF-β signalling[8]
- Truncating FBN1 variants (~20–25%) cause haploinsufficiency, often with a milder or neonatal Marfan phenotype; severity relates to variant class and domain location[8]
- Aortic root aneurysm is the cardinal manifestation; prophylactic surgery typically at 4.5–5.0 cm (lower threshold with family history of dissection, growth >3 mm/yr, or pregnancy planning)[8]
- Beta-blockers and ARBs (losartan) reduce haemodynamic wall stress and may slow aortic root growth rate[8]
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TGFBR2
~50% of LDS; TGFBR1 ~30% more | Aorta
Loeys-Dietz Syndrome | ECM / Matrix
TGF-β receptor / signalling | AD
Autosomal Dominant | Predominantly Missense | Dominant Negative | - ~50% of Loeys-Dietz syndrome (TGFBR1 accounts for a further ~30%); predominantly missense variants in the kinase or ligand-binding domain[17]
- Paradoxically, these dominant negative receptor variants increase (not decrease) TGF-β pathway signalling via compensatory upregulation, driving aortic wall remodelling[17]
- More aggressive aortopathy than Marfan: aneurysms throughout the arterial tree (intracranial, descending, visceral arteries); prominent arterial tortuosity[17]
- Intervention thresholds are lower: aortic root surgery at 3.5–4.0 cm in adults (vs. 4.5–5.0 cm for FBN1-Marfan); earlier intervention may be needed in children with rapid progression[17]
- Diagnostic clues: bifid uvula or cleft palate, hypertelorism, craniosynostosis, facial features more pronounced than typical Marfan syndrome[17]
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COL3A1
Rare; ~1 in 50,000–200,000 | Aorta
Vascular Ehlers-Danlos Syndrome | ECM / Matrix
Type III collagen | AD
Autosomal Dominant | Predominantly Missense (Gly substitutions) | Dominant Negative | - Predominantly missense variants, glycine substitutions in Gly-X-Y repeats of the type III procollagen triple-helical domain are the most common and most severe variant class[18]
- Glycine substitution prevents normal triple-helix folding → dominant negative heterotrimers disrupt vascular collagen matrix; truncating variants (NMD) cause milder haploinsufficiency phenotype[18]
- Risk of spontaneous arterial, bowel, and uterine rupture, often without preceding detectable aneurysm; many events are fatal[18]
- Invasive vascular procedures should be avoided unless life-saving; celiprolol (partial β2-agonist) reduces arterial events; branch vessel surgery preferred over open repair when intervention is unavoidable[18]
- Median survival significantly reduced (~48 years); pregnancy carries high risk of uterine rupture and arterial dissection[18]
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GLA
~0.5–1% of unexplained HCM; 1 in 40,000 males | Storage
Fabry Disease | Lysosomal
Lysosomal enzyme (α-Gal A) | XLD
X-Linked Dominant | Missense & Truncating (phenotype-linked) | Loss of Function | - X-linked dominant: hemizygous males are typically affected earlier and more severely, with classic Fabry presenting in childhood or adolescence and late-onset (cardiac) variants presenting in adulthood; heterozygous females can also be clinically affected, ranging from asymptomatic to severe depending on the X-inactivation pattern[14]
- Variant type predicts phenotype: severe missense or truncating variants with <1% residual enzyme activity → classic multisystem Fabry; specific missense variants (e.g., p.Ala143Thr) with partial residual activity → cardiac (late-onset) variant[14]
- Mechanism: α-galactosidase A deficiency → lysosomal Gb3 accumulation in cardiomyocytes, endothelium, kidneys, and neurons → progressive multi-organ damage[14]
- CMR hallmark: inferolateral mid-wall LGE (basal segments) in a non-ischaemic pattern, this distinctive pattern should prompt Fabry screening in any unexplained HCM[14]
- Disease-modifying therapy available: ERT (agalsidase-alfa or -beta) slows progression; migalastat (oral chaperone) effective for amenable missense variants (check amenability database)[14]
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LAMP2
Rare; important HCM phenocopy | Storage
Danon Disease | Lysosomal
Lysosomal membrane / autophagy | XLD
X-Linked Dominant | Predominantly Truncating (frameshift, splice, nonsense) | Loss of Function | - X-linked dominant with marked sex difference: males develop a massive HCM phenotype (wall thickness 30–40 mm), Wolff-Parkinson-White syndrome, and progressive heart failure in the 2nd–3rd decade, early death without transplantation[15]
- Predominantly truncating variants (frameshift, nonsense, splice-site) causing complete LAMP2 protein loss; females (one normal allele) develop later-onset and less severe cardiomyopathy[15]
- Mechanism: LAMP2 deficiency impairs macroautophagy → accumulation of glycogen-containing autophagic vacuoles in cardiomyocytes and skeletal muscle[15]
- Associated features: skeletal myopathy, intellectual disability (predominantly males), elevated CK; short PR interval/WPW on ECG in a young male with a massive HCM phenotype is a key diagnostic clue[15]
- No disease-modifying therapy; early transplant evaluation is essential for affected males, ideally before irreversible multi-organ progression in the 3rd decade[15]
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EMD
Rare; ~1 in 100,000 males | Storage
Emery-Dreifuss MD (X-linked) | Nuclear Envelope
Nuclear envelope (emerin) | XLR
X-Linked Recessive | Truncating & Missense | Loss of Function | - X-linked recessive (emerin): males clinically affected; female carriers usually unaffected but may develop conduction disease or cardiomyopathy in middle age due to skewed X-inactivation[10]
- Mix of truncating (~60%) and missense (~40%) variants; truncating variants tend to produce more severe disease through complete emerin loss[10]
- Classic triad (in order of appearance): early joint contractures (elbow, Achilles, cervical spine) → humeroperoneal muscle wasting → cardiac conduction disease[10]
- Cardiac manifestations: atrial standstill, complete AV block, AF, SCD risk is significant even without LV systolic dysfunction; pacemaker and ICD are commonly required[9][10]
- LMNA mutations (autosomal dominant EDMD) cause an identical cardiac phenotype, genetic testing is essential to distinguish X-linked from AD forms, as family implications differ fundamentally[10]
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MT-TL1
~1 in 5,000–10,000 | Storage
Mitochondrial Cardiomyopathy / MELAS | Mitochondria
Mitochondrial tRNA | Mit
Mitochondrial | Point mutation (m.3243A>G) | Loss of Function | - m.3243A>G in mitochondrial tRNA-Leu(UUR) is the most prevalent mitochondrial disease variant; maternally inherited (no paternal transmission)[16]
- A specific mtDNA point mutation, impairs mitochondrial tRNA aminoacylation, globally reducing mitochondrial protein synthesis in cells with high energy demand; not a conventional nuclear missense variant[16]
- Heteroplasmy (proportion of mutant mitochondria in a given tissue) determines phenotypic severity: low levels → isolated diabetes/deafness; high levels → full MELAS with stroke-like episodes, cardiomyopathy, lactic acidosis[16]
- Cardiac phenotype (HCM > DCM) may be the dominant initial manifestation, multisystem features (diabetes, sensorineural deafness, maternal family history) should be actively sought and may prompt the diagnosis[16]
- Avoid metformin (inhibits mitochondrial complex I); blood heteroplasmy levels may underestimate cardiac and muscle heteroplasmy; serial cardiac surveillance is essential; coenzyme Q10 used empirically[16]
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