To date over mutations in KCNQ have
To date, over 250 mutations in KCNQ1 have been found to be linked to LQT1  and new LQT1 causing mutations continue to be identified. The vast majority of KCNQ1 mutations are single nucleotide substitutions (missense) or small insertion/deletions that localize to the S1-S6 transmembrane domains [5,18,35,36]. One study assessing 600 LQT1 patients found that approximately 66.2% of KCNQ1 mutations (75.3% of mutation carriers) were identified in the membrane-spanning segments (approximately 1/3 in the pore loop or adjacent transmembrane regions), 31.2% (24.3% of mutation carriers) in the C terminus, and only 2.6% (0.4% of mutation carriers) in the N terminus . Importantly, these data are consistent with the results from another clinical study . Mutations in the transmembrane, linker, and pore region of KCNQ1 are usually defined as high-probability disease-causing mutations that tend to cause severe cardiac events in patients at younger ages compared to mutations in the COOH terminal region [37–41].
Genotype-phenotype correlations Existing evidence to date indicates that genetic background may influence the severity of the disease. The mutation type, specific location, and degree of dysfunction play a critical role in the clinical course of LQT1. Moss et al. reported that LQT1 patients with transmembrane mutations and dominant-negative ion current effects had a longer corrected QT (QTc) interval and a higher frequency of cardiac events than individuals with mutations in other regions or mutations resulting in haploinsufficiency, and these genetic risks were independent of traditional clinical risk factors and drug therapy . More recently, a retrospective study assessing genotype-phenotype correlations in 110 infant mutation carriers from LQT1 families also reported that carriers of the Cathepsin K Activity Fluorometric Assay Kit negative Y111C mutation presented with a tendency towards more severe heart rate reduction and postnatal QTc prolongation than carriers of the R518X nonsense mutation . Shimuzu et al. studied 95 patients carrying 27 KCNQ1 mutations (19 in transmembrane regions and eight in the COOH terminus) . They found that patients with transmembrane mutations had longer QTc, higher T-wave alterations, and more frequent LQTS-related cardiac events (including syncope, cardiac arrest, or sudden cardiac death) than those with C-terminal mutations, though the frequency of TdP was not different between the two study groups. In addition, most of the first cardiac events occurred before the age of 15 years in the LQT1 patients (particularly in males) with transmembrane mutations, whereas only half of the LQT1 patients with C-terminal mutations suffered their first cardiac events before the age of 15. Other retrospective data also indicate that missense cytoplasmic-loop mutations , pore mutations , and some specific point mutations, such as A341V, in KCNQ1[44,45] are associated with a longer QT interval and result in an increased risk of cardiac events and severe clinical phenotypes. In contrast to these studies, however, a study assessing 294 LQT1 patients with KCNQ1 gene mutations demonstrated that there were no significant differences in clinical presentation, ECG parameters, and cardiac events among LQT1 patients by 40 years of age with KCNQ1 mutations in different locations . One possible explanation for this discrepancy is that the criteria for KCNQ1 mutation type and position were different between their studies. LQT1 patients with transmembrane mutations (including those in the C-loop) were also found to be more sensitive to sympathetic stimulation and achieved a pronounced benefit from treatment with β-blockers compared to the patients with C-terminal mutations [43,47]. Therefore, the avoidance of strenuous exercise, in particular swimming, diving, or competitive sports, is recommended for LQT1 patients, especially younger males. Silent mutations and compound mutations are also important genetic factors that affect the phenotype of LQT1. Approximately 25–36% of genetically positive patients with LQT1 may have a normal QTc range (defined as<440ms) without any clinical symptoms at rest [47,48]. Although these silent mutation-positive patients have a significantly lower risk of life-threatening cardiac events compared to those with phenotypic patterns, it should not be assumed that such a phenotype-negative individual who has a normal QTc is not affected by the cardiac disease. A number of risk assessments have confirmed that lethal arrhythmias can occur in these apparently healthy silent mutation carriers without any premonitory sign, especially during emotional stress or physical exertion [49–51]. There is also growing evidence that compound mutation carriers have a more severe cardiac phenotype compared with individuals carrying a single mutation [35,42,52–54]. Compound mutations were found to be associated with longer QTc, more frequent cardiac events, and earlier onset of cardiac events. Therefore, the management of patients with such mutations should be tailored to their increased risk for arrhythmias .