Linkage Evidence for a Two-Locus Inheritance of LQT-Associated Seizures in a Multigenerational LQT Family With a Novel KCNQ1 Loss-of-Function Mutation.

Harald Prüss,Herbert Schulz,Ann-Kathrin Ruppert,Thomas Sander,Stefan H Heinemann,Guido Gessner,Wilhelm Rimpau,Franz Rüschendorf

doi:10.3389/fneur.2019.00648

Abstract

Mutations in several genes encoding ion channels can cause the long-QT (LQT) syndrome with cardiac arrhythmias, syncope and sudden death. Recently, mutations in some of these genes were also identified to cause epileptic seizures in these patients, and the sudden unexplained death in epilepsy (SUDEP) was considered to be the pathologic overlap between the two clinical conditions. For LQT-associated KCNQ1 mutations, only few investigations reported the coincidence of cardiac dysfunction and epileptic seizures. Clinical, electrophysiological and genetic characterization of a large pedigree (n = 241 family members) with LQT syndrome caused by a 12-base-pair duplication in exon 8 of the KCNQ1 gene duplicating four amino acids in the carboxyterminal KCNQ1 domain (KCNQ1dup12; p.R360_Q361dupQKQR, NM_000218.2, hg19). Electrophysiological recordings revealed no substantial KCNQ1-like currents. The mutation did not exhibit a dominant negative effect on wild-type KCNQ1 channel function. Most likely, the mutant protein was not functionally expressed and thus not incorporated into a heteromeric channel tetramer. Many LQT family members suffered from syncopes or developed sudden death, often after physical activity. Of 26 family members with LQT, seizures were present in 14 (LQTplus seizure trait). Molecular genetic analyses confirmed a causative role of the novel KCNQ1dup12 mutation for the LQT trait and revealed a strong link also with the LQTplus seizure trait. Genome-wide parametric multipoint linkage analyses identified a second strong genetic modifier locus for the LQTplus seizure trait in the chromosomal region 10p14. The linkage results suggest a two-locus inheritance model for the LQTplus seizure trait in which both the KCNQ1dup12 mutation and the 10p14 risk haplotype are necessary for the occurrence of LQT-associated seizures. The data strongly support emerging concepts that KCNQ1 mutations may increase the risk of epilepsy, but additional genetic modifiers are necessary for the clinical manifestation of epileptic seizures.

Highlights

Prolonged QT intervals are the diagnostic hallmark of inherited long-QT (LQT) syndromes which comprise a growing number of mutations in ion channels, with the gene encoding the voltage-gated potassium channel KCNQ1 (Kv7.1) being the most common LQT gene (OMIM #192500: LQT1) [1]
While the clinical overlap between cardiac arrhythmias and epilepsy has been well-established for LQT-associated channelopathies related to the SCN5A and KCNH2 genes [5, 7, 17], and epileptic seizures were found in 12% of patients with LQT syndrome associated with KCNQ1 mutations [4], little is known about the detailed mechanisms and additional genetic risk factors leading to coincidental affection of heart and brain
A recent study used next-generation sequencing in epilepsy patients with cardiac dysfunction or sudden death to explore the role of already known and novel candidate genes associated with epilepsy and sudden unexpected death in epilepsy (SUDEP) [18]

Summary

Introduction

Prolonged QT intervals are the diagnostic hallmark of inherited long-QT (LQT) syndromes which comprise a growing number of mutations in ion channels, with the gene encoding the voltage-gated potassium channel KCNQ1 (Kv7.1) being the most common LQT gene (OMIM #192500: LQT1) [1]. LQT syndrome by KCNQ1 mutations has long been considered as a cardiac disease with the risk of ventricular arrhythmias and sudden cardiac death, resulting from prolongation of the cardiac action potential. In patients with LQT1 syndrome due to KCNQ1 mutations, clinical seizures were consistently observed [3, 4]. The same study used a mouse model carrying a human KCNQ1 knock-in mutation which resulted in cardiac arrhythmias and in seizures and sudden unexpected death in epilepsy (SUDEP). The model reflects emerging evidence from clinical cohorts of patients with LQT syndrome in which there is an increased association with epilepsy and seizure-like phenotypes, in particular in the related LQT disease with mutations in the gene encoding the voltagegated potassium channel KCNH2 (Kv11.1, hERG1) [6, 7]

Methods

Results

Conclusion