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

IF 1.7 4区 医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS
Pace-Pacing and Clinical Electrophysiology Pub Date : 2025-03-01 Epub Date: 2025-02-06 DOI:10.1111/pace.15145
Hongyu Liu, Zhenhong Jiang, Yang Shen, Ying Shao, Yuhao Su, Daowu Wang, Ramon Brugada, Kui Hong
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引用次数: 0

Abstract

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.

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来源期刊
Pace-Pacing and Clinical Electrophysiology
Pace-Pacing and Clinical Electrophysiology 医学-工程:生物医学
CiteScore
2.70
自引率
5.60%
发文量
209
审稿时长
2-4 weeks
期刊介绍: Pacing and Clinical Electrophysiology (PACE) is the foremost peer-reviewed journal in the field of pacing and implantable cardioversion defibrillation, publishing over 50% of all English language articles in its field, featuring original, review, and didactic papers, and case reports related to daily practice. Articles also include editorials, book reviews, Musings on humane topics relevant to medical practice, electrophysiology (EP) rounds, device rounds, and information concerning the quality of devices used in the practice of the specialty.
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