Topological Distribution of KCNH2 Variants and Genotype-Phenotype Relationship in Patients With Long QT Syndrome.

Aims: The aim of this study was to investigate the topological distribution of single nucleotide variants (SNVs) in the KCNH2 gene from patients with type 2 long QT syndrome (LQT2) and to explore the genotype-phenotype relationships.

Methods: Information on KCNH2 variants in LQT2 patients was retrospectively obtained from the HGMD, ClinVar, and PubMed databases through October 2022. Pathogenicity of SNV was classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Unpaired t-tests and Fisher's exacts were used to analyze the SNV distributions across structural and functional domains, and their correlation with clinical phenotypes.

Results: A total of 2826 variants were obtained; 2152 were SNVs, 1328 of which were nonsynonymous SNVs (nsSNVs) associated with LQT2. Enrichment analysis revealed that 602 pathogenic (P) and likely pathogenic (LP) nsSNVs were significantly enriched at S5, H5, S6, Extra3, and Extra4. In addition, 759 nsSNVs and 289 P/LP nsSNVs within function domain were enriched at the per-arnt-sim (PAS) and selectivity filter (SF) functional domain. Clinical data revealed that patients with nsSNVs enriched at the N-terminal, S5-H5-S6 region and PAS domain were associated with an increased risk of syncope. Moreover, nsSNVs located at the N-terminal, S5-H5-S6 region, and PAS, SF domains were associated with an increased risk of life-threatening cardiac events, including Torsade de Pointes (TdP) and sudden cardiac death (SCD), and were predominantly female.

Conclusion: KCNH2 nsSNVs located at the N-terminal, S5-H5-S6 region, and the PAS and SF functional domains are associated with an increased risk of life-threatening cardiac events in LQT2 patients.