Compound Mutations A Common Cause of Severe Long-QT Syndrome

Department of Physiology, University of Utah, 95 South 2000 East, Salt Lake City, UT 84112-5000, USA.
Circulation (Impact Factor: 14.43). 04/2004; 109(15):1834-41. DOI: 10.1161/01.CIR.0000125524.34234.13
Source: PubMed


Long QT syndrome (LQTS) predisposes affected individuals to sudden death from cardiac arrhythmias. Although most LQTS individuals do not have cardiac events, significant phenotypic variability exists within families. Probands can be very symptomatic. The mechanism of this phenotypic variability is not understood.
Genetic analyses of KVLQT1, HERG, KCNE1, KCNE2, and SCN5A detected compound mutations in 20 of 252 LQTS probands (7.9%). Carriers of 2 mutations had longer QTc intervals (527+/-54 versus 489+/-44 ms; P<0.001); all had experienced cardiac events (20 of 20 [100%] versus 128 of 178 [72%]; P<0.01) and were 3.5-fold more likely to have cardiac arrest (9 of 16 [56%] versus 45 of 167 [27%]; P<0.01; OR, 3.5; 95% CI, 1.2 to 9.9) compared with probands with 1 or no identified mutation. Two-microelectrode voltage clamp of Xenopus oocytes was used to characterize the properties of variant slow delayed rectifier potassium (I(Ks)) channels identified in 7 of the probands. When wild-type and variant subunits were coexpressed in appropriate ratios to mimic the genotype of the proband, the reduction in I(Ks) density was equivalent to the additive effects of the single mutations.
LQTS-associated compound mutations cause a severe phenotype and are more common than expected. Individuals with compound mutations need to be identified, and their management should be tailored to their increased risk for arrhythmias.

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Available from: Michael C Sanguinetti, Jan 28, 2015
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    • "Long QT syndrome is usually an autosomal dominant disease, but, occasionally, multiple mutations in a single gene or in different genes could be found in 5–10% of the patients with LQTS (21, 22). Patients with multiple mutations could exhibit a longer QTc compared with those with a single mutation and such patients are also at ∼3.5-fold increased risk for life-threatening cardiac events (21, 22) "
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    ABSTRACT: Primary cardiac arrhythmias are often caused by defects, predominantly in the genes responsible for generation of cardiac electrical potential, i.e., cardiac rhythm generation. Due to the variability in underlying genetic defects, type, and location of the mutations and putative modifiers, clinical phenotypes could be moderate to severe, even absent in many individuals. Clinical presentation and severity could be quite variable, syncope, or sudden cardiac death could also be the first and the only manifestation in a patient who had previously no symptoms at all. Despite usual familial occurrence of such cardiac arrhythmias, disease causal genetic defects could also be de novo in significant number of patients. Long QT syndrome (LQTS) is the most eloquently investigated primary cardiac rhythm disorder. A genetic defect can be identified in ∼70% of definitive LQTS patients, followed by Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Brugada syndrome (BrS), where a genetic defect is found in <40% cases. In addition to these widely investigated hereditary arrhythmia syndromes, there remain many other relatively less common arrhythmia syndromes, where researchers also have unraveled the genetic etiology, e.g., short QT syndrome (SQTS), sick sinus syndrome (SSS), cardiac conduction defect (CCD), idiopathic ventricular fibrillation (IVF), early repolarization syndrome (ERS). There exist also various other ill-defined primary cardiac rhythm disorders with strong genetic and familial predisposition. In the present review we will focus on the genetic basis of LQTS and its clinical management. We will also discuss the presently available genetic insight in this context from Saudi Arabia.
    Frontiers in Pediatrics 11/2013; 1:39. DOI:10.3389/fped.2013.00039
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    • "This is clearly suggestive that KCNE1 can modify or contribute to native human ventricular IKr. Additionally, there are conflicting reports regarding the effect of D85N polymorphism on recombinant IKs (KCNQ + KCNE1) with both reduced current amplitude (Westenskow et al. 2004; Nishio et al. 2009) and no change in amplitude (Nielsen et al. 2007; Nof et al. 2011) reported, whereas this mutation clearly reduces IhERG (Nishio et al. 2009; Nof et al. 2011). Thus, although KCNE1 mutations associated with QT interval prolongation may normally exert their effect through modulation of IKs (McCrossan and Abbott 2004; Modell and Lehmann 2006), effects mediated through IKr modulation can also occur. "
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    ABSTRACT: human Ether-à-go-go-Related Gene (hERG) encodes the pore-forming subunit of cardiac rapid delayed rectifier K(+) current (I Kr) channels, which play important roles in ventricular repolarization, in protecting the myocardium from unwanted premature stimuli, and in drug-induced Long QT Syndrome (LQTS). KCNE1, a small transmembrane protein, can coassemble with hERG. However, it is not known how KCNE1 variants influence the channel's response to premature stimuli or if they influence the sensitivity of hERG to pharmacological inhibition. Accordingly, whole-cell patch-clamp measurements of hERG current (I hERG) were made at 37°C from hERG channels coexpressed with either wild-type (WT) KCNE1 or with one of three KCNE1 variants (A8V, D76N, and D85N). Under both conventional voltage clamp and ventricular action potential (AP) clamp, the amplitude of I hERG was smaller for A8V, D76N, and D85N KCNE1 + hERG than for WT KCNE1 + hERG. Using paired AP commands, with the second AP waveform applied at varying time intervals following the first to mimic premature ventricular excitation, the response of I hERG carried by each KCNE1 variant was reduced compared to that with WT KCNE1 + hERG. The I hERG blocking potency of the antiarrhythmic drug quinidine was similar between WT KCNE1 and the three KCNE1 variants. However, the I hERG inhibitory potency of the antibiotic clarithromycin and of the prokinetic drug cisapride was altered by KCNE1 variants. These results demonstrate that naturally occurring KCNE1 variants can reduce the response of hERG channels to premature excitation and also alter the sensitivity of hERG channels to inhibition by some drugs linked to acquired LQTS.
    11/2013; 1(6):e00175. DOI:10.1002/phy2.175
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    • "Esparza-Gordillo et al. (2006), Westra et al. (2010) and Bresin et al. (2013) Atypical haemolytic uraemic syndrome CFH CD46 or CFI or C3 or THBD Sullivan et al. (2011), Bresin et al. (2013) and Fan et al. (2013) Epidermolysis bullosa simplex* KRT14 KRT5 Padalon-Brauch et al. (2012) Junctional epidermolysis bullosa COL17A1 LAMB3 Floeth and Bruckner-Tuderman (1999) Long QT syndrome* KCNQ1 KCNH2 or KCNE1 or SCN5A Schwartz et al. (2003), Westenskow et al. (2004), Tester et al. (2005) and Itoh et al. (2010) Long QT syndrome* KCNH2 SCN5A or KCNE1 Schwartz et al. (2003), Westenskow et al. (2004) and Tester et al. (2005) Long QT syndrome* SCN5A SNTA1 or KCNE1 Westenskow et al. (2004) and Hu et al. (2013) Haemochromatosis* HFE HAMP or TFR2 Merryweather-Clarke et al. (2003), Jacolot et al. (2004), Island et al. (2009), Altès et al. (2009) and Del-Castillo-Rueda et al. (2012) Kallmann syndrome* PROK2 PROKR2 Cole et al. (2008), Sarfati et al. (2010) and Shaw et al. (2011) Kallmann syndrome NELF KAL1 or TACR3 Xu et al. (2011) and Quaynor et al. (2011) Kallmann syndrome PROKR2 KAL1 Dodé et al. (2006), Canto et al. (2009) and Shaw et al. (2011) Kallmann syndrome KAL1 TACR3 or WDR11 or CHD7 Quaynor et al. (2011) and Shaw et al. (2011) Normosmic idiopathic hypogonadotrophic hypogonadism GNRH KAL1 Quaynor et al. (2011) Normosmic idiopathic hypogonadotrophic hypogonadism WDR11 GNRHR Quaynor et al. (2011) Normosmic idiopathic hypogonadotrophic hypogonadism FGFR1 GNRHR or PROKR2 or FGF8 or KAL1 or GPR54 Raivio et al. (2009), Sykiotis et al. (2010) and Shaw et al. (2011) Systemic amyloid A amyloidosis TNFRSF1A MEFV Cigni et al. (2006) and Mereuta et al. (2013) Hum Genet "
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    ABSTRACT: Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as 'reduced (or incomplete) penetrance'. Reduced penetrance is not uncommon; indeed, there are many known examples of 'disease-causing mutations' that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.
    Human Genetics 07/2013; 132(10). DOI:10.1007/s00439-013-1331-2 · 4.82 Impact Factor
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