Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long QT syndrome (LQTS) is a cardiac disorder with an abnormality of cardiac rhythm associated with sudden death especially in younger, apparently healthy individuals. If there is no clear cause of death detectable during comprehensive coroner's inquest (autopsy-negative cases), you have to consider LQTS and other heritable arrhythmia syndromes. A molecular genetic screening regarding mutations in associated genes can help to ensure the cause of death and to protect affected family members. Genetic testing of LQTS, currently performed mainly by sequencing, is still very expensive and time consuming. With this study we present a rapid and reasonable method for the simultaneously screening of some of the most common mutations associated with LQTS, focused on the KCNQ1 and KCNH2 genes. With the method of SNaPshot minisequencing, a total of 58 mutations were analyzed in four multiplex assays which were successfully established and optimized. The comparison with samples previously analyzed by direct sequencing showed concordance. Furthermore, autopsy-negative cases were tested but no mutations could be observed in any of the specimen. The presented method is well suitable for LQTS mutation screening. An enhancement to further mutations and population-based investigations regarding mutation frequencies should be the aim of prospective studies.
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PMID:Long QT syndrome mutation detection by SNaPshot technique. 2176 75

We report on an asymptomatic 10-year-old boy who had a short QT interval (corrected QT interval, 260 ms). Short QT syndrome (SQTS) was detected in a school screening program for heart disease and the patient was subsequently diagnosed as having N588K mutation in the KCNH2 gene. Quinidine prolonged the QT interval, but not the QU interval. During treadmill exercise stress test, QT and QU intervals responded differently to heart rate changes, suggesting a mechanoelectrical hypothesis for the origin of the U wave. Although rare, attention should be paid to SQTS, which is associated with potential fatal arrhythmias.
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PMID:Short QT syndrome in a boy diagnosed on screening for heart disease. 2533 96

Congenital long QT syndrome (LQTS) is characterized by QT prolongation with predisposition to life-threatening arrhythmia. There have been sporadic reports of LQTS coexisting with more common forms of congenital heart disease (CHD). However, the diagnosis of LQTS when CHD is present may be confounded by several common variables including postoperative electromechanical factors predisposing to ventricular arrhythmia, intrinsic, and postoperative QRS abnormalities. This report documents a single-center experience with patients who have both genetically confirmed LQTS and CHD to examine their modes of presentation and factors associated with making the diagnosis of LQTS in this patient population, as well as potential confounding variables that may mask or delay both LQTS diagnosis and initiation of therapy. A retrospective review was performed of subjects with confirmed LQTS and associated CHD from 1999 to January 2017. Genetic analysis was performed predominantly using commercially available panel testing. A chart review included detailed analysis of electrocardiograms, 24-hour 3-lead rhythm monitors and exercise stress test tracings as well as the genetic test reports. QT intervals were measured using Bazett's formula. Eleven patients were identified. Four patients had LQTS type 1, 6 had LQTS type 2, and 1 had a disease-associated mutation in KCNQ1 and a variant of unknown significance in KCNH2 gene. Two patients had positive cascade screening. Arrhythmia presentations of the LQTS were at both extremes of the cohort age range (in-utero and midchildhood age). There was a seeming overrepresentation of conotruncal anomalies and/or arch anomalies, with 7 of the 11 patients. In conclusion, the diagnosis of LQTS may be challenging in the setting of CHD (a prolonged ST segment may be helpful), and high index of suspicion is required. The overall incidence of LQTS in CHD appears extremely rare, but the diagnosis and true incidence may be masked by confounding electrocardiogrpahic findings and other variables common in CHD.
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PMID:Genotype Positive Long QT Syndrome in Patients With Coexisting Congenital Heart Disease. 2853 74

Sequence variants in the ion channel genes KCNH2 and SCN5A may cause the cardiac disorder long QT syndrome (LQTS). This disorder is associated with incomplete penetrance and variable expression in KCNH2- or SCN5A-mutation carriers. Common genetic variants, if associated with a mutation, may affect the severity of this cardiac disorder. This study identified rare mutations in the cardiac ion channel genes KCNH2 and SCN5A in a SCD case, as well as in a LQTS-affected family with a history of SCD. Moreover, common variants were found to occur together within the same genes. These findings support the concept that common single-nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels can directly modulate the functional effect of mutations and therefore enhance or weaken the risk of cardiac events.
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PMID:Influence of genetic modifiers on sudden cardiac death cases. 2921 56

Establishing a definition of short QT syndrome (SQTS), including symptomatology and QT-interval duration, is still a work in progress. However, it is clear , that SQTS is a rare, life-threatening, inherited heart disease presenting as sudden cardiac death (SCD) or aborted SCD in 34% and a family history of SCD in 15%. Genetic testing is important in diagnosing the disease, but to date a causative mutation is found in <25%. A benign variety of the disease has been observed in children with atrial fibrillation and a KCNH2-V141M mutation, and recently a mutation in the cardiac Cl/HCO3 exchanger AE3 was found to cause SQTS. Issues related to measuring and correcting the QT interval for heart rate has made it difficult to rely entirely on QT duration for the diagnosis of SQTS. In order to establish the diagnosis on firmer grounds, symptoms, family history, and genetic testing need to be considered. Although the benefit of insertion of an implantable cardioverter-defibrillator as secondary prophylaxis against SCD in a patient with SQTS is well documented, the benefit as primary prophylaxis is controversial and not proven by solid data. In 2 recent similar studies involving 115 patients with approximately 5 years of follow-up, insertion of an implantable cardioverter-defibrillator in 40 patients saved the lives of 12, 11 who had presented with cardiac arrest and 1 with syncope. No appropriate shocks were delivered in any patients who did not have a history of either syncope or cardiac arrest. Currently quinidine is the only drug that has undergone any clinical testing.
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PMID:Diagnosis and management of short QT syndrome. 2950 67

In patients with Long QT Syndrome (LQTS), mutations in the potassium channel KCNH2 gene increase seizure susceptibility with missense mutations involving the pore region of the gene acting as a positive predictor of seizures. Seizures are less commonly reported in patients with carboxyl (C')-terminus mutations. This case report describes a young man who presented with syncope followed by a first seizure and was found to have LQTS caused by a pathogenic carboxyl-terminus deletion/frameshifting mutation of the KCNH2 gene. He later had a second seizure after anti-seizure medication taper. This mutation has not previously been reported associated with seizures. Our case suggests that, in patients with this type of C'-terminus mutation and a first seizure or syncope, there is a susceptibility to epilepsy. As inherited congenital heart disease may be a risk factor for sudden unexpected death in epilepsy (SUDEP), attention to all specific genetic markers in a young patient with QT prolongation and a first seizure could guide the use of anti-seizure medication to reduce the risk of SUDEP.
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PMID:New onset seizures in a patient with Long QT Syndrome (LQTS2) and a pathogenic carboxyl-terminus frameshift variant of the KCNH2 gene. 2973 26

Down syndrome (DS) is the most common autosomal chromosome anomaly. DS is frequently associated with congenital heart disease (CHD). Patients with DS have 40-60% chance of having CHD. It means that CHD in DS is not only due to trisomy 21 and there are some other genetic factors underlying CHD in DS children. In this study, a total of 240 DNA samples from patients were analyzed including 100 patients with CHD only, 110 patients having CHD along with DS and 30 patients with isolated DS. A cardiovascular gene panel consisting of probes for 406 genes was used to screen DNA samples of all 240 patients for mutation identification. All variants were annotated and common variants were obtained. Briefly, 28 common variants (variants common in two or more than two individuals) were obtained in a group of samples containing DNA from DS patients having CHD as well, 63 variants were found to be unique to DS group of samples and 73 variants have been identified in patients with CHD only. In order to identify genomic variations determining the risk for CHD in DS, only those variants present in DS-CHD group and absent in isolated CHD and/or isolated DS group were considered for further analysis. Variants specific to DS-CHD group were further evaluated based on expression and function data and pathogenicity of the variant of interest. We have implicated mutations in GATA3, KCNH2, ENG, FLNA, and GUSB genes as an underlying risk factor for CHD in DS patients.
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PMID:Targeted Next-Generation Sequencing of 406 Genes Identified Genetic Defects Underlying Congenital Heart Disease in Down Syndrome Patients. 3010 68

The congenital long QT syndrome (LQTS) is a cardiac disorder characterized by a prolonged QT interval on the electrocardiogram and an increased susceptibility to ventricular arrhythmias and sudden cardiac death. A frequent cause for LQTS is mutations in the KCNH2 gene (also known as the human ether-a-go-go-related gene or hERG), which reduce or modulate the potassium current IKr and hence alter cardiac repolarization. In a patient with a clinically diagnosed LQTS, we identified the mutation L69P in the N-terminal PAS (Per-Arnt-Sim) domain of hERG. Functional expression in HEK293 cells shows that a homotetrameric hERG channel reconstituted with only mutant subunits exhibits a drastically reduced surface expression of the channel protein thus leading to a diminished hERG current. Unlike many other mutations in the hERG-PAS domain the negative impact of the L69P substitution cannot be rescued by facilitated protein folding at a lower incubation temperature. Further, co-expression of wt and mutant monomers does not restore either wt like surface expression or the full hERG current. These results indicate L69P is a dominant negative mutation, with deficits which most likely occurs at the level of protein folding and subsequently inhibits trafficking to the plasma membrane. The functional deficits of the mutant channel support the clinical diagnosis of a LQTS.
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PMID:The mutation L69P in the PAS domain of the hERG potassium channel results in LQTS by trafficking deficiency. 3225 72


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