SCN5A – Familial Long QT Syndrome

Familial long QT syndrome type 3 (LQT3) is an autosomal dominant cardiac channelopathy caused by mutations in the SCN5A gene, which encodes the Nav1.5 α-subunit of the cardiac sodium channel (SCN5A, familial long QT syndrome). Affected individuals exhibit prolonged ventricular repolarization, leading to QT interval prolongation on ECG and risk of syncope and sudden cardiac death.

Genetic studies have identified SCN5A variants in approximately 8 % of unrelated LQTS probands (n ≈ 21) (PMID:10973849). Among these, the de novo c.4865G>A (p.Arg1622Gln) mutation was first described in an infant with severe LQT3 who displayed markedly delayed inactivation and bursting channel behaviour (PMID:9506831). Segregation analyses in multiple kindreds have confirmed autosomal dominant transmission with penetrance in affected relatives (≥ 5) and absence in healthy controls.

The variant spectrum in SCN5A–LQT3 is dominated by missense changes clustered in the S4–S5 and DIII–DIV linker regions, with recurrent alleles such as p.Arg1622Gln. Functional assays in Xenopus oocytes and mammalian cells demonstrate that these mutations confer a gain-of-function by impairing fast inactivation and generating a persistent late sodium current, thereby prolonging action potential duration.

Biophysical characterization of p.Arg1622Gln channels revealed a threefold prolongation of macroscopic current decay and increased single-channel open times compared to wild-type (PMID:9495298; PMID:9686753). These findings align with the clinical phenotype of QT prolongation and support a primary mechanism of delayed repolarization.

No robust evidence disputes the SCN5A–familial LQT3 association. Sodium channel blockers such as lidocaine and mexiletine normalize inactivation kinetics in vitro and have been used successfully in genotype-specific therapy, underscoring the clinical utility of molecular diagnosis.

Key take-home: SCN5A gain-of-function mutations cause familial LQT3 through delayed inactivation and late sodium current, justifying genotype-directed therapy with sodium channel blockers.

References

• FEBS letters • 1998 • A de novo missense mutation of human cardiac Na+ channel exhibiting novel molecular mechanisms of long QT syndrome. PMID:9506831
• Circulation • 2000 • Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. PMID:10973849
• Circulation • 1998 • Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. PMID:9495298
• Circulation research • 1998 • Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha- and beta1-subunits. PMID:9686753

Evidence Based Scoring (AI generated)