SCN5A – Long QT Syndrome Type 3

Long QT syndrome type 3 (LQT3) is an autosomal dominant cardiac channelopathy caused by gain-of-function mutations in SCN5A, the gene encoding the Nav1.5 α‐subunit of the cardiac sodium channel (Gene Symbol). Affected individuals exhibit prolonged ventricular repolarization, syncope, and risk of sudden cardiac death due to late sodium current (INa) during phase 2 of the action potential (MONDO_0011377).

Initial linkage in a large Dutch pedigree demonstrated a heterozygous 1795insD insertion segregating with 26 nocturnal sudden deaths and conduction disease among 114 carriers, including bradycardia-dependent QT prolongation and sinus node dysfunction (26 affected relatives)[PMID:25696119]. Additional reports describe over 30 unrelated probands harboring pathogenic SCN5A variants with autosomal dominant segregation and de novo events, including recurrent indel and missense alleles.

Missense mutations predominate in LQT3, often clustering in the C-terminal domain and activation/inactivation gating regions. A notable example is c.3575G>A (p.Arg1192Gln), identified in a Korean infant with mixed LQT3/DCM phenotypes treated with ICD therapy (1 proband)[PMID:22519808]. Other recurrent variants include p.Arg1643His and p.Gln1475Pro, each shown to alter fast inactivation kinetics and increase late INa.

Functional studies using heterologous expression and patient‐derived hiPSC‐CMs confirm that LQT3 mutations destabilize inactivation, yielding persistent late currents. The D1790G mutation shifts steady‐state inactivation by –16 mV in α+β1 channels without generating sustained current, while R1643H hiPSC‐CMs exhibit action potential prolongation, early afterdepolarizations, and drug responsiveness consistent with clinical phenotypes ([PMID:9686753], [PMID:26803770]). Phenytoin selectively rescues gating defects of Q1475P channels, whereas mexiletine restores surface expression but less effectively corrects late INa ([PMID:32339567]).

Conflicting evidence arises from the E1053K variant, which in one pedigree was homozygous in asymptomatic members and required an additional promoter deletion to explain sudden death, highlighting variable penetrance and modifier effects ([PMID:28391114]).

Integrating genetic segregation with mechanistic data establishes a definitive SCN5A–LQT3 association. Gain-of-function mutations reliably reproduce human phenotypes in cellular models and respond predictably to sodium channel blockers. Key takeaway: genetic testing for SCN5A LQT3 variants informs risk stratification and guides targeted therapy with sodium channel blockers and device implantation.

References

• Netherlands heart journal • 2002 • A large family characterised by nocturnal sudden death. PMID:25696119
• Pacing and clinical electrophysiology • 2012 • Long QT syndrome and dilated cardiomyopathy with SCN5A p.R1193Q polymorphism: cardioverter-defibrillator implantation at 27 months. PMID:22519808
• Basic research in cardiology • 2016 • Human iPS cell model of type 3 long QT syndrome recapitulates drug-based phenotype correction. PMID:26803770
• Journal of molecular and cellular cardiology • 2020 • A distinct molecular mechanism by which phenytoin rescues a novel long QT 3 variant. PMID:32339567
• Forensic science international • 2017 • Genotype-phenotype dilemma in a case of sudden cardiac death with the E1053K mutation and a deletion in the SCN5A gene. PMID:28391114
• Circulation research • 1998 • Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha- and beta1-subunits. PMID:9686753

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