Clinical and Functional Reappraisal of Alleged Type 5 Long QT Syndrome-Causative Genetic Variants in the KCNE1-Encoded minK β-Subunit

Abstract 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 To reassess the clinical and electrophysiological (EP) phenotypes associated with KCNE1 variants detected in a single-center LQTS cohort. Methods Retrospective analysis of 1,026 LQTS patients was used to identify those individuals with isolated KCNE1 ultra-rare variants [minor allele frequency (MAF) Results Overall, six KCNE1 variants were identified in 38/1,026 (3.7%) LQTS patients. Based on existing data, two 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 IKs current) and was upgraded to a LP variant, the three remaining KCNE1 VUS (p.Arg67Cys-KCNE1, p.Arg67His-KCNE1, and 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 of 444±19 ms, and 27% with a maladaptive QTc response during exercise/recovery). Conclusion This study indicates that p.Ser28Leu-KCNE1 may be a 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.