The main results of the present study from 600 patients having a spectrum of KCNQ1 mutations derived from 3 LQTS registries are significantly higher cardiac event rates in patients with transmembrane mutations and in patients with mutations having a putative dominant-negative effect on the repolarizing IKs current. The effect of these genetically determined factors is independent of traditional clinical risk factors and of β-blocker therapy.
Since 1995, when the first 2 genes responsible for LQTS were identified,11,12
molecular genetic studies have revealed a total of 9 forms of congenital LQTS caused by mutations in genes involving potassium channel (LQT-1, -2, -5, -6, and -7), sodium channel (LQT-3, -9), and calcium channel proteins (LQT-8) as well as a membrane-adapter protein (LQT-4).2,13
Genotype–phenotype studies have enabled us to stratify risk and to treat more specifically patients with LQT-1, LQT-2, and LQT-3 subtypes of this genetic disorder. LQT-1, the most common form of LQTS, accounts for ≈50% of genotyped patients4,14
and has more variable expressivity and incomplete penetrance than the other forms.15
Mutation location and knowledge of the functional effects of the mutation provide additional risk information beyond the clinical risk factors and the genotype, at least for LQT-1, and this information should contribute to improved risk stratification and more focused management of these higher-risk patients.
Mutations in KCNQ1 are responsible for defects in the slowly activating component of the delayed rectifier current IKs
This current is the main repolarizing current at increased heart rate and is highly sensitive to catecholamines.3
We speculate that IKs
channels with transmembrane mutations might have reduced responsiveness to the regulatory β
-adrenergic signaling of the ion-conduction pathway with more impairment of shortening of the QTc with exercise-related tachycardia than mutations in the C-terminus region.
channels result from the coassembly of 4 KCNQ1-encoded subunits. A mutated gene encodes a protein with aberrant function, and the presence of both normal and abnormal proteins in the ion channel contributes to a >50% reduction in ion channel function (dominant-negative effect). An alternative mechanism of reduced repolarizing KCNQ1 K+
current is the inability of mutated subunits to coassemble with normal gene products, such as occurs with a trafficking defect, resulting in a ≤50% reduction in channel function (haploinsufficiency). With only 1 exception,17
this is the case for all studied truncating mutations leading to incomplete proteins. Our assumption that truncated proteins (based on frameshift nonsense mutations) lead to haploinsufficiency seems justified. The biophysical effect of missense mutations is unpredictable, and both haploinsufficiency and dominant-negative effects have been described. In the absence of reported biophysical studies, missense mutations were classified as unknown.
Previous attempts to identify a genotype–phenotype relationship for KCNQ1 mutations failed to reach consensus on the clinical outcome of the type and site of mutations.7,8
Relatively small numbers and different ethnic background of the previously reported patients with the LQT-1 genotype might be responsible for the discrepant results. The present larger study allows us to demonstrate for the first time that the biophysical effect clearly affects the clinical outcome (ie, dominant-negative mutations are associated with a more severe phenotype than are mutations conferring haploinsufficiency , even after adjustment for relevant covariates ). The risk observed in 19 subjects with 3 different intron mutations was not quite significant (P
=0.06), possibly because of small numbers, but the magnitude of the risk effect was similar to the risk accompanying transmem-brane mutations. Although these intron mutations produced splice-site alterations predicted to affect the transmembrane portion of the ion channel, we used a separate categorization of intron mutations in view of the limited understanding of the structural alterations and functional effects resulting from these exon-skipping intron mutations.
A few additional findings from this large genotype–phenotype study of type-1 LQTS patients emphasize high risk for first cardiac events during adolescence, a crossover in risk by sex at approximately age 13 years, and a lower rate of first cardiac events in the adult years than in the younger years. These findings are not especially new,18,19
but the present study highlights their presence in type-1 LQTS.
The present study used the biophysical function of mutations reported in the literature in only a portion of the mutations that were included (see references associated with Table 1 in the online-only Data Supplement
). The published studies were from many different laboratories with the use of different cellular heterologous expression systems involving Xenopus
oocytes and other cells at both room and physiological temperatures. Although such nonuniform testing may have contributed to some inconsistency in the categorized biophysical function, the finding of a significantly higher event rate in mutations with dominant-negative than with haploinsufficient effects (hazard ratio, 2.26; P
<0.001) is unlikely to have resulted from the nonuniform testing. Unfortunately, we did not have the resources to perform such uniform testing in all 77 mutations presented in the present study.
Once a mutation was identified in KCNQ1, thorough genetic sequencing was not performed routinely in all the ion channel genes to look for second mutations. Thus, some of the patients included in the analysis may have had a second mutation in addition to the identified KCNQ1 mutation. It is estimated that ≈10% of genotype LQTS patients may carry a second mutation, and those with >1 mutation could contribute to some of the findings in our study. In addition, it is possible that some of the reported mutations () are simply uncommon sequence mutations, but this is relatively unlikely because all the subjects in the present study were derived from families in which the proband had QTc prolongation not due to a known cause.
The outcome analyses included subjects from families with a known KCNQ1 mutation who died suddenly and unexpectedly at a young age and were classified as LQTS-related death with the same mutation that was present in the family. It is possible that a few of these subjects could have died from a non-LQTS cause or had an LQTS mutation different from the family mutation, but we think the error rate is likely to be small. The number of deaths and aborted cardiac arrest events is small, and there is insufficient power to evaluate the risk association of the genotype characteristics with these endpoint events in a multivariate time-dependent model.
The present study confirms that in patients with type-1 LQTS, longer QTc intervals are associated with higher cardiac event rates and that male patients are generally younger than female patients at first cardiac events.20,21
The new findings from the present study are that transmembrane mutations and mutations with dominant-negative functional effect adversely influence the outcome of this disorder independent of traditional clinical risk factors and β
-blocker therapy. The present study was not designed to assess the effectiveness of different therapies in patients with KCNQ1 mutations. The findings presented do not provide justification for using specific genotype characteristics to identify patients for implanted defibrillator therapy.