Genotype-phenotype correlation of 139 p.Gln530Ter-KCNQ1 patients with inherited long QT syndrome

Aleksei A Savelev; Nina Larsson; Pia Dahlberg; Alex H Christensen; Cecilie Bugge; Ivana Bulatovic; Teodora Gardovic; Anneli Svensson; Erik Ljungström; Minna Markljung; Michael Ringborn; Catarina Lundin; Ilan Goldenberg; Scott McNitt; Bronislava Polonsky; Claus Graff; Wojciech Zareba; Kristina H Haugaa; Pyotr G Platonov

doi:10.1016/j.hrthm.2026.03.1911

Genotype-phenotype correlation of 139 p.Gln530Ter-KCNQ1 patients with inherited long QT syndrome

Heart Rhythm. 2026 Mar 23:S1547-5271(26)02166-1. doi: 10.1016/j.hrthm.2026.03.1911. Online ahead of print.

Authors

Aleksei A Savelev¹, Nina Larsson², Pia Dahlberg³, Alex H Christensen⁴, Cecilie Bugge⁵, Ivana Bulatovic⁶, Teodora Gardovic⁶, Anneli Svensson⁷, Erik Ljungström⁸, Minna Markljung⁹, Michael Ringborn¹⁰, Catarina Lundin¹¹, Ilan Goldenberg¹², Scott McNitt¹², Bronislava Polonsky¹², Claus Graff¹³, Wojciech Zareba¹², Kristina H Haugaa⁵, Pyotr G Platonov¹⁴

Affiliations

¹ Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden. Electronic address: aleksei.savelev@med.lu.se.
² Department of Clinical Genetics, Pathology and Molecular Diagnostics, Skåne University Hospital, Lund, Sweden.
³ Department of Cardiology, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden.
⁴ Department of Cardiology, Copenhagen University Hospital - Herlev-Gentofte/Rigshospitalet, Herlev, Denmark, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵ ProCardio Center for Innovation, Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, and Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁶ Department of Cardiology, Karolinska University Hospital, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
⁷ Department of Cardiology and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
⁸ Arrhythmia Clinic, Skåne University Hospital, Lund, Sweden.
⁹ Department of Internal Medicine, Växjö Regional Hospital, Växjö, Sweden.
¹⁰ Thoracic Center, Karlskrona, Sweden.
¹¹ Department of Clinical Genetics, Laboratory Medicine, Lund University, Lund, Sweden; Office for Medical Services, Skåne University Hospital, Lund, Sweden.
¹² University of Rochester Medical Center, Rochester, New York.
¹³ Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
¹⁴ Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden.

PMID: 41881367
DOI: 10.1016/j.hrthm.2026.03.1911

Abstract

Background: Variants in the KCNQ1 underlie type 1 long QT syndrome. The clinical manifestations are influenced by the specific KCNQ1 pathogenic variant.

Objective: We aimed to describe the phenotype in patients found to possess the p.Gln530Ter-KCNQ1 pathogenic variant common in Scandinavian patients with long QT syndrome.

Methods: Clinical characteristics of p.Gln530Ter-KCNQ1 variant-positive patients from 6 university hospital registries in Sweden, Denmark, Norway, and the United States were compared with carriers of other KCNQ1 pathogenic variants (non-p.Gln530Ter-KCNQ1) and gene-negative controls. Cardiac events (CEs) encompassed syncope of unknown origin and ventricular arrhythmias (VAs) (episodes of torsades de pointes, appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, or sudden cardiac death).

Results: The p.Gln530Ter-KCNQ1, non-p.Gln530Ter-KCNQ1, and control groups included 139 (65% female; 24% probands; mean age at end of follow-up 51 ± 20 years), 194 (65% female; mean age 44 ± 19), and 717 individuals (55% female; mean age 39 ± 24), respectively. CEs by 60 years of age were reported in 30 of the p.Gln530Ter-KCNQ1 group (22%; of those 5 VA, all nonfatal), 46 of the non-p.Gln530Ter-KCNQ1 group (24%; 4 VA, all nonfatal), and 81 of controls (11%; no VA). In the p.Gln530Ter-KCNQ1 group, CE occurred at a significantly older age than in the non-p.Gln530Ter-KCNQ1 group (44 ± 22 vs 31 ± 22; P = .02). Before 30 years of age, CE risk in the p.Gln530Ter-KCNQ1 group did not differ from that in controls (adjusted hazard ratio 1.11 [95% confidence interval 0.65-1.89]; P = .707) and was significantly lower than in the non-p.Gln530Ter-KCNQ1 group. After 30 years of age, CE risk in the p.Gln530Ter-KCNQ1 group increased significantly (adjusted hazard ratio 3.21 [95% confidence interval 1.49-6.92]; P = .003, compared with controls) and did not differ from the non-p.Gln530Ter-KCNQ1 group.

Conclusion: The p.Gln530Ter-KCNQ1 variant is associated with a later onset of CE than other KCNQ1 pathogenic variants.

Keywords: Gln530Ter; Haploinsufficiency; KCNQ1; Q530X; Stop codon; Sudden cardiac death; Syncope; Type 1 long QT syndrome; Ventricular arrhythmia.