Rare pathogenic mutation of KCNH2 p.D501N associated with early-onset malignant long QT syndrome

Long QT syndrome (LQTS) is a life-threatening inherited channelopathy that is prone to triggering torsades de pointes (TdP), ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death.

Whole-exome sequencing (WES) was performed on a proband with LQTS, and candidate variants were validated by Sanger sequencing. Bioinformatics methods were used to analyze the pathogenicity of the variants.

A proband who was a 16-year-old girl presented with a prolonged QT interval, TdP, VT, and VF. She carried the de novo KCNH2 p.D501N mutation, which is localized to the S3 helix of the voltage-sensing domain of Kv11.1 and predicted to be "deleterious" by the SIFT, PolyPhen-2, and MetaSVM algorithms. Secondary structure prediction showed that this mutation increases the proportion of alpha helices and extended strands, while decreasing the proportion of the random coil. In addition, this substitution induces buried charge replacement, breakage of the buried salt bridge formed by p.D501 and p.R534, and cavity expansion (with p.R537 moving markedly outward). It also leads to abnormal changes in the interactions among p.R537, p.R534, p.Y493, p.V533, and p.W497, resulting in spatial structure displacement and deflection. Compared with wild-type KCNH2, KCNH2 p.D501N exhibits decreased molecular weight, total number of negatively charged residues (Arg + Lys), oxygen content, charged residues (B: Asx, D: Asp, E: Glu, H: His, K: Lys, R: Arg, Z: Glx), and acidic residues (B + D + E + Z), while it shows increased theoretical isoelectric point (PI), hydrogen and nitrogen content, isoelectric point, net charge, and reduced probability of the formation of inclusion bodies.

The KCNH2 p.D501N mutation significantly alters the secondary/tertiary structure and physicochemical properties of the K_v11.1 protein, which may impair the cardiac I_Kr current and ultimately induce early-onset malignant LQT2 in a Chinese family. This condition requires ICD therapy combined with long-term β-blocker administration and potassium-magnesium supplementation.