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