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

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

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.

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).

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.

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