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

Figures

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  Figure 1. Familial pedigree of the proband with KCNH2 p.D501N. This figure depicts the pedigree structure of the family involved in the study. The proband (II:1) is a 16-year-old girl diagnosed with early-onset malignant LQT2, who presented with recurrent syncope, torsades de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF), which required implantable cardioverter-defibrillator (ICD) implantation. Her father (I:1) and mother (I:2) had no clinical manifestations related to LQTS (e.g., syncope, palpitations, sudden cardiac death) and showed no abnormalities in electrocardiography (ECG) and echocardiography. A genetic testing confirmed that only the proband carried the heterozygous KCNH2 p.D501N mutation, while the parents did not, indicating that this is a de novo mutation. Symbols: □ = male; ○ = female; ● = affected female and disease (proband); arrow = proband.

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  Figure 2. Ambulatory eAmbulatory electrocardiographic and intracardiac electrogram characteristics of the proband. Ambulatory electrocardiogram tracings show an episode of torsade de pointes (TdP) (A), frequent ventricular premature beats in bigeminy originating from the left ventricular outflow tract (B), rhythm progression from ventricular tachycardia/ventricular fibrillation to non-sustained ventricular tachycardia followed by restoration of sinus rhythm and recurrent torsade de pointes (C), and frequent multifocal non-sustained ventricular tachycardia (D). Intracardiac electrogram tracings from the ICD demonstrate frequent premature ventricular beats progressing to ventricular tachycardia and ventricular fibrillation, which are successfully terminated by ICD shocks (E,F).

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  Figure 3. A conservation analysis of the KCNH2 p.D501 residue across 100 vertebrate species. This figure illustrates the evolutionary conservation of the amino acid residue at position 501 of the KCNH2-encoded Kv11.1 protein, analyzed using the “Vertebrate Multiz Alignment and Conservation (100 Species)” tool in the UCSC Genome Browser. (1) A schematic diagram of KCNH2 protein transcripts: The D501 residue is conserved across different transcripts (e.g., D161 in short transcript, D405 in intermediate transcript, and D501 in full-length transcript), indicating its functional importance. (2) Cross-species alignment results: The D501 residue (marked with a red star) is highly conserved among 100 vertebrate species, including primates (e.g., Gorilla, Rhesus), mammals (e.g., Elephant, Dog), birds (e.g., Saker falcon, Chicken), reptiles (e.g., American alligator), amphibians (e.g., X. tropicalis), and fish (e.g., Zebrafish, Tetraodon). All species retain an aspartic acid (D) at this position, except for the proband's mutation (D→N). Functional prediction tools (CADD score = 32, REVEL score = 0.915, red bars) consistently classified the p.D501N variant as deleterious, strongly supporting its…

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  Figure 4. Missense3D-predicted structural changes induced by the KCNH2 p.D501N mutation. This figure illustrates the tertiary structure abnormalities of the Kv11.1 protein caused by the KCNH2 p.D501N mutation, as predicted by Missense3D (based on PDB ID: 5VAO, the experimental 3D structure of the Kv11.1 voltage-sensing domain). (A–D) Evaluation of the impact on the amino acid spatial structure between wild-type KCNH2 (D501 in blue font) and mutant KCNH2 p.D501N (N501 in red font) from different spatial angles. In the same figure, we simultaneously present the spatial structure of amino acids around wild-type D501 and mutant N501, as well as the spatial structural changes induced by the mutation, and observe and assess the impact of the mutation on the surrounding amino acid space from multiple perspectives. The wild-type KCNH2 (D501) is a buried negatively charged residue that forms a stable salt bridge with Arg534 (R534), and its spatial structure is displayed in yellow font and gray amino acid graphics. The KCNH2 p.D501N mutation replaces the buried charged aspartic acid (D501) with uncharged asparagine (N501), resulting in buried charge replacement and breakage of the D501-R534 salt…