SCN5A – Short QT Syndrome

SCN5A has been reported in multi-gene arrhythmia panels including cohorts with short QT syndrome (SQTS), but evidence for a causal role in SQTS is insufficient. In a pediatric review of SQTS, SCN5A was listed among six genes identified in nearly 60% of families, yet no SCN5A variant showed segregation with a short QT phenotype and none were functionally demonstrated to shorten repolarization ([PMID:28303324]). Moreover, an expert reappraisal using the ClinGen framework classified SCN5A as lacking valid evidence for SQTS pathogenesis ([PMID:34557911]).

Functional studies of SCN5A variants, such as c.5299A>G (p.Ile1767Val), show altered sodium channel recovery from inactivation but have not been linked to action potential shortening or SQTS clinical traits ([PMID:12650885]). No animal models or rescue experiments have reproduced a short QT interval with SCN5A mutations. Taken together, genetic and experimental data do not support SCN5A as a disease gene for SQTS.

Key take-home: SCN5A is not recommended for inclusion in SQTS genetic testing panels due to lack of segregation and functional evidence.

References

• Clinical research in cardiology • 2017 • Short QT syndrome in pediatrics. PMID:28303324
• European Heart Journal • 2022 • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. PMID:34557911
• Cardiovascular Research • 2003 • A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics. PMID:12650885

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