Progressive familial heart block: genes and variants

Genes linked to Progressive familial heart block

• SCN5A: Sodium channel protein type 5 subunit alpha

  Its rapid inward sodium current drives the upstroke of the cardiac action potential and enables fast electrical conduction through atrial, ventricular, and conduction-system tissue. Pathogenic variants can cause long-QT syndrome type 3, Brugada syndrome, conduction disease, and overlapping arrhythmia phenotypes.

  4 disease-causing and 11 uncertain variants in SCN5A are linked to Progressive familial heart block.

• DSP: Desmoplakin

  It anchors intermediate filaments to desmosomes, allowing mechanically stressed tissues such as myocardium and epidermis to maintain strong cell-cell adhesion. Pathogenic variants can cause arrhythmogenic or dilated cardiomyopathy and a range of cardiocutaneous disorders.

  1 disease-causing and 0 uncertain variants in DSP are linked to Progressive familial heart block.

Weakly linked (only a few uncertain records): KCNH2 and CASQ2.

Known disease-causing variants in Progressive familial heart block

Same protein, different disease

• Brugada syndrome is also caused by SCN5A variants; they fall mostly in different places as the Progressive familial heart block variants (24 disease-causing).
• Cardiac arrhythmia is also caused by SCN5A variants; they fall mostly in different places as the Progressive familial heart block variants (17 disease-causing).
• Long QT syndrome is also caused by SCN5A variants; they fall mostly in different places as the Progressive familial heart block variants (16 disease-causing).
• Atrial fibrillation, familial, 10 is also caused by SCN5A variants; they fall mostly in different places as the Progressive familial heart block variants (3 disease-causing).
• Ventricular fibrillation, paroxysmal familial, type 1 is also caused by SCN5A variants; they fall mostly in different places as the Progressive familial heart block variants (3 disease-causing).
• Arrhythmogenic right ventricular dysplasia is also caused by DSP variants; they fall mostly in different places as the Progressive familial heart block variants (6 disease-causing).
• Arrhythmogenic cardiomyopathy with wooly hair and keratoderma is also caused by DSP variants; they fall mostly in different places as the Progressive familial heart block variants (6 disease-causing).

Diseases related to Progressive familial heart block

• Dilated cardiomyopathy, also linked to DSP and SCN5A
• Cardiac arrhythmia, also linked to DSP and SCN5A
• Long QT syndrome, also linked to SCN5A
• Hypertrophic cardiomyopathy, also linked to DSP
• Primary dilated cardiomyopathy, also linked to SCN5A
• Brugada syndrome, also linked to SCN5A
• Epilepsy, also linked to SCN5A
• Atrial fibrillation, familial, 10, also linked to SCN5A
• Arrhythmogenic right ventricular dysplasia, also linked to DSP
• Idiopathic pulmonary fibrosis, also linked to DSP
• Sick sinus syndrome 2, autosomal dominant, also linked to SCN5A
• Arrhythmogenic cardiomyopathy with wooly hair and keratoderma, also linked to DSP

Frequently asked questions

Which genes are linked to Progressive familial heart block?

In CATVariant, Progressive familial heart block is linked to 2 analyzed proteins: SCN5A (Sodium channel protein type 5 subunit alpha) and DSP (Desmoplakin).

How many genetic variants are linked to Progressive familial heart block?

23 variants: 5 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 14 are of uncertain significance or have conflicting reports.

Which uncertain variants in Progressive familial heart block 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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