Abstract Body: Aims: The aim of this study was to investigate the topological distribution of single nucleotide variants (SNVs) in KCNH2 in patients with long QT syndrome (LQTS) and to explore the relationships between genotypes and phenotypes.
Methods: Information on KCNH2 variants in LQTS patients was retrospectively obtained from the HGMD, ClinVar and PubMed databases through October 2022. SNV pathogenicity was classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Unpaired t tests and Fisher's exact tests were used to analyze the SNV distributions across structural and functional domains, and their correlations with clinical phenotypes.
Results: A total of 2826 variants were obtained; 2152 were SNVs, 1328 of which were non-synonymous SNVs (nsSNVs) associated with LQTS. Enrichment analysis revealed that 602 pathogenic (P) and likely pathogenic (LP) nsSNVs were significantly enriched in the Cyto2, S5, S6, H5, and Extra3. In addition, 759 nsSNVs were enriched in the Per-Arnt-Sim (PAS) and selectivity filter (SF) functional domain. The P and LP nsSNVs remained enriched in the PAS, SF, and cyclic nucleotide binding domain (cNBD). Clinical data showed that patients with nsSNVs located at S5-H5-S6, PAS and SF regions were associated with increased risk of life-threatening cardiac events, including Torsade de Pointes and sudden cardiac death, and were predominantly female. Furthermore, nsSNVs enriched in N-terminus region, S5-H5-S6 region and PAS domain were associated with an increased risk of syncope.
Conclusion: The KCNH2 nsSNVs located at the S5-H5-S6 region, and the PAS and SF domains are associated with increased risk of life-threatening cardiac events.