Key result
Digenic KCNH2 and SCN5A mutations linked to early-onset LQTS and sinoatrial node dysfunction.
Case Report
The study identifies digenic heterozygous mutations in KCNH2 and SCN5A as a genetic basis for early-onset long QT syndrome combined with sinoatrial node dysfunction.
May inform genetic evaluation in early-onset LQTS with SAN dysfunction; leaves open validation in larger cohorts.
Introduction Long QT syndrome (LQTS) is a life‐threatening inherited channelopathy, and prolonged QT intervals easily trigger malignant arrhythmias, especially torsades de pointes and ventricular fibrillation. Materials and methods The proband with overlapped phenotypes of LQTS and sinoatrial node dysfunction underwent some necessary examinations, including echocardiography, electrocardiogram (ECG), and Holter monitoring. Next, whole‐exome sequencing was performed, and candidate genes were validated by Sanger sequencing. RNA secondary structure and protein physical‐chemical parameter analyses were used to predict the possible structural change of the proteins induced by the mutations. Results We identified the digenic heterozygous mutations of KCNH2 p.307_308del (NM_001204798, c.921_923del) and SCN5A p.R1865H (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. Subsequently, she occurred with obvious sinus arrest with persistent ventricular pacing of implantable cardioverter‐defibrillator. The heterozygous SCN5Ap.R1865H was carried by her father and sister but not carried by I:2. II:1 carried with KCNH2 p.307_308del as a de novo mutation, but not existed in other family members. RNA secondary structure of KCNH2 p.307_308del showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Na v 1.5 protein property, SCN5A p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index. Conclusions The digenic heterozygous KCNH2 and SCN5A mutations were associated with young early‐onset long QT syndrome and sinoatrial node dysfunction.
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Yang et al. (2021) conducted a case report in Long QT syndrome and sinoatrial node dysfunction. Whole-exome sequencing was evaluated on Identification of genetic mutations. Digenic heterozygous mutations of KCNH2 (p.307_308del) and SCN5A (p.R1865H) were identified in a young female proband and associated with early-onset long QT syndrome and sinoatrial node dysfunction.
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