Clinical and functional reappraisal of alleged type 5 long QT syndrome: Causative genetic variants in the KCNE1-encoded minK β-subunit

Background: KCNE1 loss-of-function variants cause type 5 long QT syndrome (LQT5). However, most alleged LQT5-causative KCNE1 variants were identified before the true rate of background genetic variation was appreciated fully. Objective: The purpose of this study was to reassess the clinical and electrophysiological (EP) phenotypes associated with KCNE1 variants detected in a single-center LQTS cohort. Methods: Retrospective analysis of 1026 LQTS patients was used to identify those individuals with isolated KCNE1 ultra-rare variants (minor allele frequency [MAF] <0.0004 in the Genome Aggregation Database [gnomAD]). After classification according to American College of Medical Genetics (ACMG) guidelines, variants of uncertain significance (VUS) were characterized in vitro using whole-cell patch-clamp technique. Lastly, the clinical phenotype observed in ACMG pathogenic/likely pathogenic (P/LP) KCNE1-positive individuals was assessed. Results: Overall, 6 KCNE1 variants were identified in 38 of 1026 LQTS patients (3.7%). Based on existing data, 2 KCNE1 variants (p.Asp76Asn-KCNE1 and p.Arg98Trp-KCNE1) were classified as P/LP. Whereas the p.Ser28Leu-KCNE1 VUS conferred a loss-of-function EP phenotype (72% reduction in I_Ks current) and was upgraded to an LP variant, the 3 remaining KCNE1 VUS (p.Arg67Cys-KCNE1, p.Arg67His-KCNE1, p.Ser74Leu-KCNE1) were indistinguishable from wild type. Collectively, the phenotype observed in p.Ser28Leu-KCNE1-, p.Asp76Asn-KCNE1-, and p.Arg98Trp-KCNE1-positive individuals (n = 22) was relatively weak (91% asymptomatic; average QTc 444 ± 19 ms; 27% with a maladaptive QTc response during exercise/recovery). Conclusion: This study indicates that p.Ser28Leu-KCNE1 may be an LQT5-causative substrate analogous to p.Asp76Asn-KCNE1 and p.Arg98Trp-KCNE1. However, the weak phenotype and cumulative gnomAD MAF (42/141,156) associated with these P/LP variants suggest LQT5/KCNE-LQTS may be a more common/weaker form of LQTS than anticipated previously.