Familial isolated dilated cardiomyopathy: genes and variants

Genes linked to Familial isolated dilated cardiomyopathy

• TNNT2: Troponin T, cardiac muscle

  It anchors the cardiac troponin complex to tropomyosin and helps translate calcium-dependent conformational changes into controlled actin-myosin interaction. Pathogenic variants can cause hypertrophic, dilated, or restrictive cardiomyopathy and alter arrhythmic risk.

  3 disease-causing and 0 uncertain variants in TNNT2 are linked to Familial isolated dilated cardiomyopathy.

• ABCC9: ATP-binding cassette sub-family C member 9

  A regulatory subunit of ATP-sensitive potassium (KATP) channels, partnering with KCNJ11 or KCNJ8 to control channel activation. It is a multi-pass membrane protein with important roles in cardiac and smooth-muscle excitability, and altered ABCC9 function is associated with cardiomyopathy, atrial fibrillation, and neurodevelopmental syndromes.

  0 disease-causing and 0 uncertain variants in ABCC9 are linked to Familial isolated dilated cardiomyopathy.

• ACTC1: Actin, alpha cardiac muscle 1

  Its cardiac alpha-actin filaments form the core of the sarcomeric thin filament and provide the track against which myosin generates force. Pathogenic variants can cause hypertrophic or dilated cardiomyopathy and selected congenital heart defects.

  0 disease-causing and 0 uncertain variants in ACTC1 are linked to Familial isolated dilated cardiomyopathy.

• BAG3: BAG family molecular chaperone regulator 3

  It coordinates chaperone-assisted protein quality control and autophagy, particularly in mechanically stressed cardiac and skeletal muscle. Pathogenic variants can impair sarcomere maintenance and cause dilated cardiomyopathy or myofibrillar myopathy.

  0 disease-causing and 0 uncertain variants in BAG3 are linked to Familial isolated dilated cardiomyopathy.

• CSRP3: Cysteine and glycine-rich protein 3

  It localizes to the cardiac Z-disc and participates in mechanosensing and maintenance of sarcomere structure under mechanical load. Pathogenic variants can cause hypertrophic or dilated cardiomyopathy by disrupting cardiac structural signaling.

  0 disease-causing and 0 uncertain variants in CSRP3 are linked to Familial isolated dilated cardiomyopathy.

• DES: Desmin

  Its desmin filaments mechanically integrate sarcomeres with the nucleus, mitochondria, and cell junctions in striated muscle. Pathogenic variants cause desmin-related myopathy and can produce cardiomyopathy, conduction disease, and skeletal-muscle weakness.

  0 disease-causing and 0 uncertain variants in DES are linked to Familial isolated dilated cardiomyopathy.

• DMD: Dystrophin

  Its dystrophin product mechanically links the actin cytoskeleton of muscle fibers to the extracellular matrix and stabilizes the sarcolemma during contraction. Severe loss causes Duchenne muscular dystrophy, while variants preserving partial function more often cause Becker muscular dystrophy.

  0 disease-causing and 0 uncertain variants in DMD are linked to Familial isolated dilated cardiomyopathy.

• MYH6: Myosin-6

  Its alpha-myosin motor contributes to ATP-dependent force generation in the cardiac sarcomere, particularly in atrial myocardium. Pathogenic variants can cause cardiomyopathy, congenital heart defects, and selected conduction-system disorders.

  0 disease-causing and 0 uncertain variants in MYH6 are linked to Familial isolated dilated cardiomyopathy.

• MYH7: Myosin-7

  Its beta-myosin motor converts ATP hydrolysis into force within cardiac and slow-skeletal-muscle sarcomeres. Pathogenic variants are major causes of hypertrophic and dilated cardiomyopathy and can also produce inherited skeletal myopathies.

  0 disease-causing and 0 uncertain variants in MYH7 are linked to Familial isolated dilated cardiomyopathy.

• MYPN: Myopalladin

  It links sarcomeric and cytoskeletal proteins at the Z-disc and intercalated-disc regions, helping transmit mechanical force and maintain muscle architecture. Pathogenic variants can cause dilated or hypertrophic cardiomyopathy and, in some cases, skeletal myopathy.

  0 disease-causing and 0 uncertain variants in MYPN are linked to Familial isolated dilated cardiomyopathy.

• PLN: Phospholamban

  It tonically restrains SERCA2a-mediated calcium reuptake into the cardiac sarcoplasmic reticulum, with phosphorylation relieving this inhibition during adrenergic stimulation. Pathogenic variants can destabilize calcium cycling and cause dilated or arrhythmogenic cardiomyopathy.

  0 disease-causing and 0 uncertain variants in PLN are linked to Familial isolated dilated cardiomyopathy.

• PSEN1: Presenilin-1

  Its catalytic activity within gamma-secretase cleaves APP and many other membrane proteins, including Notch receptors. Pathogenic variants alter amyloid-beta production and are the most common known cause of autosomal dominant early-onset Alzheimer disease.

  0 disease-causing and 0 uncertain variants in PSEN1 are linked to Familial isolated dilated cardiomyopathy.

• RBM20: RNA-binding protein 20

  It directs cardiac alternative splicing of TTN and numerous calcium-handling and sarcomeric transcripts. Pathogenic variants can produce a highly arrhythmogenic form of dilated cardiomyopathy through widespread disruption of cardiac RNA processing.

  0 disease-causing and 0 uncertain variants in RBM20 are linked to Familial isolated dilated cardiomyopathy.

• SDHA: Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial

  It catalyzes oxidation of succinate to fumarate while transferring electrons into respiratory-chain complex II, directly linking the TCA cycle with oxidative phosphorylation. Biallelic deficiency can cause mitochondrial disease, while heterozygous loss-of-function variants predispose to paraganglioma, pheochromocytoma, and selected gastrointestinal stromal tumors.

  0 disease-causing and 0 uncertain variants in SDHA are linked to Familial isolated dilated cardiomyopathy.

• TNNC1: Troponin C, slow skeletal and cardiac muscles

  It binds calcium during each heartbeat and shifts the troponin complex to permit actin-myosin interaction and force generation in cardiac muscle. Pathogenic variants can alter calcium sensitivity and cause hypertrophic or dilated cardiomyopathy.

  0 disease-causing and 0 uncertain variants in TNNC1 are linked to Familial isolated dilated cardiomyopathy.

• TNNI3: Troponin I, cardiac muscle

  It restrains cardiac actin-myosin interaction at low calcium and shifts position within the troponin complex when calcium binds, allowing contraction. Pathogenic variants can alter thin-filament calcium sensitivity and cause hypertrophic, restrictive, or dilated cardiomyopathy.

  0 disease-causing and 0 uncertain variants in TNNI3 are linked to Familial isolated dilated cardiomyopathy.

• TPM1: Tropomyosin alpha-1 chain

  It lies along actin filaments and helps control access of myosin to actin in response to troponin and calcium, while also stabilizing cytoskeletal actin in nonmuscle cells. Pathogenic variants can cause hypertrophic or dilated cardiomyopathy and several congenital myopathies.

  0 disease-causing and 0 uncertain variants in TPM1 are linked to Familial isolated dilated cardiomyopathy.

• TTN: Titin

  Its enormous titin polypeptide spans much of the sarcomere and provides passive elasticity, structural alignment, and mechanosensing in striated muscle. Truncating variants are among the most common genetic causes of dilated cardiomyopathy, while other variants cause diverse skeletal and cardiac myopathies.

  0 disease-causing and 0 uncertain variants in TTN are linked to Familial isolated dilated cardiomyopathy.

• VCL: Vinculin

  It links integrins and cadherins to the actin cytoskeleton at focal adhesions and adherens junctions, transmitting mechanical force between cells and matrix. Pathogenic variants can cause dilated or hypertrophic cardiomyopathy and, in some cases, skeletal myopathy.

  0 disease-causing and 0 uncertain variants in VCL are linked to Familial isolated dilated cardiomyopathy.

Weakly linked (only a few uncertain records): LDB3.

Known disease-causing variants in Familial isolated dilated cardiomyopathy

Same protein, different disease

• Hypertrophic cardiomyopathy is also caused by TNNT2 variants; they fall mostly in different places as the Familial isolated dilated cardiomyopathy variants (20 disease-causing).
• Dilated cardiomyopathy is also caused by TNNT2 variants; they fall mostly in different places as the Familial isolated dilated cardiomyopathy variants (18 disease-causing).
• Cardiomyopathy, familial restrictive, 3 is also caused by TNNT2 variants; they fall mostly in different places as the Familial isolated dilated cardiomyopathy variants (16 disease-causing).
• Primary dilated cardiomyopathy is also caused by TNNT2 variants; they fall mostly in different places as the Familial isolated dilated cardiomyopathy variants (7 disease-causing).

Diseases related to Familial isolated dilated cardiomyopathy

• Dilated cardiomyopathy, also linked to ABCC9, ACTC1, BAG3, CSRP3 and 12 more
• Hypertrophic cardiomyopathy, also linked to ACTC1, BAG3, CSRP3, MYH6 and 9 more
• Primary dilated cardiomyopathy, also linked to ACTC1, CSRP3, DES, MYH6 and 6 more
• Primary familial dilated cardiomyopathy, also linked to DES, MYH6, MYH7, RBM20 and 1 more
• Left ventricular noncompaction, also linked to ACTC1, MYH7, TNNT2 and TPM1
• Atrial septal defect, also linked to ACTC1, MYH6 and TPM1
• Cardiomyopathy, familial restrictive, 3, also linked to TNNC1, TNNI3 and TNNT2
• Primary familial hypertrophic cardiomyopathy, also linked to MYH6, MYH7 and TNNI3
• Restrictive cardiomyopathy, also linked to MYH7, TNNC1 and TNNI3
• Myofibrillar myopathy, also linked to BAG3 and DES
• Familial cardiomyopathy, also linked to MYH7 and TPM1
• Dilated cardiomyopathy 1FF, also linked to TNNC1 and TNNI3

Frequently asked questions

Which genes are linked to Familial isolated dilated cardiomyopathy?

In CATVariant, Familial isolated dilated cardiomyopathy is linked to 19 analyzed proteins: TNNT2 (Troponin T, cardiac muscle), ABCC9 (ATP-binding cassette sub-family C member 9), ACTC1 (Actin, alpha cardiac muscle 1), BAG3 (BAG family molecular chaperone regulator 3), CSRP3 (Cysteine and glycine-rich protein 3), DES (Desmin) and 13 more.

How many genetic variants are linked to Familial isolated dilated cardiomyopathy?

5 variants: 3 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial isolated dilated cardiomyopathy look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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