Key result
LQT with seizures links to a two-locus inheritance model requiring both KCNQ1dup12 and 10p14 variants.
Why the study?
Only few investigations had reported the coincidence of cardiac dysfunction and epileptic seizures for LQT-associated KCNQ1 mutations.
Observational (n=241)
This study provides evidence for a two-locus inheritance model for LQT-associated seizures, suggesting that both a KCNQ1 mutation and an additional genetic modifier (10p14 risk haplotype) are necessary for the clinical manifestation of epilepsy in these patients.
KCNQ1 mutations may link LQT arrhythmias with epilepsy; leaves open mechanistic overlap with SUDEP and needs confirmation in larger cohorts.
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.
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Prüß et al. (2019) conducted an observational in Long-QT syndrome (n=241). KCNQ1dup12 mutation and 10p14 risk haplotype was evaluated on LQTplus seizure trait. In a 241-member pedigree, 14 of 26 individuals with LQT experienced seizures, revealing a two-locus inheritance model requiring both a KCNQ1dup12 mutation and a 10p14 risk haplotype.
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