Spectrum of Mutations in Long-QT Syndrome Genes

Splawski, Igor; Shen, Jinglai; Timothy, Katherine W.; Lehmann, Michael H.; Priori, Silvia G.; Robinson, Jennifer L.; Moss, Arthur J.; Schwartz, Peter J.; Towbin, Jeffrey A.; Vincent, G; Keating, Mark T.

doi:10.1161/01.cir.102.10.1178

Cited by 1,135 publications

(772 citation statements)

References 77 publications

Supporting

Mentioning

740

Contrasting

Unclassified

Order By: Relevance

“…Compared with the results of prior studies (15), the majority (70%) of mutations identified in this study were located in the pore region and transmembrane domains S5 and S6 that are immediately adjacent to the pore, and 30% were in the C-terminus. In the report by Splawski et al (15) just 23% of 75 KCNQ1 mutations were in S5 or S6 domains or pore region.…”

Section: Discussioncontrasting

confidence: 82%

See 1 more Smart Citation

KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death

et al. 2003

View full text Add to dashboard Cite

Long QT syndrome (LQTS) is the prototype of the cardiac ion channelopathies which cause syncope and sudden death. LQT1, due to mutations of KCNQ1 (KVLQT1), is the most common form. This study describes the genotype-phenotype characteristics in 10 families with mutations of KCNQ1, including 5 novel mutations. One hundred and two families with a history of lethal cardiac events, 55 LQTS, 9 Brugada syndrome, 18 idiopathic ventricular fibrillation (IVF), and 20 acquired LQTS, were studied by single-strand conformational polymorphism (SSCP) and DNA sequence analyzes. Families found to have KCNQ1 mutations were phenotyped using ECG parameters and cardiac event history, and genotype-phenotype correlation was performed. No mutations were found in Brugada syndrome, IVF, or acquired LQTS families. Ten out of 55 LQTS families had KCNQ1 mutations and 62 carriers were identified. Mutations included G269S in domain S5; W305X, G314C, Y315C, and D317N in the pore region; A341E and Q357R in domain S6; and 1338insC, G568A and T587M mutations in the C-terminus. W305X, G314C, Q357R, 1338insC, and G568A, appeared to be novel mutations. Gene carriers were 26 ± 19 years (32 females). Baseline QTc was 0.47 ± 0.03 s (range 0.40-0.57 s) and 40% had normal to borderline QTc (≤0.46 s). Typical LQT1 T wave patterns were present in at least one affected member of each family, and in 73% of all affected members. A history of cardiac events was present in 19/62 (31%), 18 with syncope, 2 with aborted cardiac arrest (ACA) and six with sudden death (SD). Two out of 6 SDs (33%) occurred as the first symptom. No difference in phenotype was evident in pore vs. non-pore mutations. KCNQ1 mutations were limited to LQTS families. All five novel mutations produced a typical LQT1 phenotype. Findings emphasize (1) reduced penetrance of QTc and symptoms, resulting in diagnostic challenges, (2) the problem of sudden death as the first symptom (33% of those who died), and (3) genetic testing is important for Mutations in KCNQ1 are the most common cause of LQTS and over 100 mutations have been reported. In addition to the genetic heterogeneity, there is prominent phenotypic heterogeneity with reduced penetrance and variable expression, causing challenges for accurate diagnosis of some patients (9). Therefore, to identify additional mutations and further expand the genotypephenotype correlations in LQT1 we screened 102 families for mutations in KCNQ1 and correlated mutation findings with clinical features in mutation carriers. Methods Identification of LQTS patientsOne hundred and two families with cardiac ion channelopathy phenotype or acquired LQTS were referred to the Q. Isolation of genomic DNA Genomic DNA was prepared from whole blood using the DNA Isolation Kit for Mammalian Blood (Roche Diagnostic Co., Indianapolis, IN). SSCP analysisSingle-strand conformational polymorphism (SSCP) analysis was carried out as described previously (4,10). The coding region and the intron splice sites of the KCNQ1 gene were screened by SSCP analysis for mutations i...

show abstract

Section: Discussioncontrasting

confidence: 82%

“…In the report by Splawski et al (15) just 23% of 75 KCNQ1 mutations were in S5 or S6 domains or pore region. In a recent report on clinical expression of different KCNH2 (HERG) mutations (16), pore region mutations appeared to result in a more severe phenotype than other mutations.…”

Section: Discussionmentioning

confidence: 95%

KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Recent genetic studies have established a clear inverse relationship between QT interval and expression and function of potassium channels. Gene defects resulting in loss of function of voltage‐gated potassium channels, for example, are associated with long QT syndromes: LQT1 (KCNQ1) and LQT2 (KCNH2), encoding α‐subunits of the potassium channels I Ks and I Kr ; LQT5 (KCNE1) and LQT6 (KCNE2), encoding β‐subunits of the potassium channels I Ks and I Kr ; and LQT7 (KCNJ2), encoding the inward rectifier potassium channel Kir2.1 12, 13, 14, 15, 16, 17…”

Section: Discussionmentioning

confidence: 99%

Obstructive Sleep Apnea and Circulating Potassium Channel Levels

Zhou

Prasad

et al. 2016

JAHA

View full text Add to dashboard Cite

BackgroundCardiac arrhythmias and sudden cardiac death are more frequent in patients with obstructive sleep apnea (OSA). OSA is associated with QT prolongation, and QT prolongation is an independent risk factor for sudden cardiac death. Because QT prolongation can be mediated by potassium channel loss of function, we tested whether OSA or continuous positive airway pressure therapy altered mRNA expression of circulating white blood cell potassium channels.Methods and ResultsIn total, 28 patients with OSA newly diagnosed by polysomnogram and 6 participants without OSA were enrolled. Potassium channel levels in white blood cells at baseline and at a 4‐week follow‐up visit were compared. There was a significant inverse correlation between the severity of the OSA stratified by apnea–hypopnea index and mRNA expression of the main potassium channels assessed: KCNQ1 (r=−0.486, P=0.007), KCNH2 (r=−0.437, P=0.016), KCNE1 (r=−0.567, P=0.001), KCNJ2 (r=−0.442, P=0.015), and KCNA5 (r=−0.468, P=0.009). In addition, KCNQ1, KCNH2, and KCNE1 inversely correlated with the oxygen desaturation index 4. After 4 weeks of continuous positive airway pressure therapy, circulating KCNQ1 and KCNJ2 were increased 1.4±0.4‐fold (P=0.040) and 2.1±1.4‐fold (P=0.046) in the moderate OSA group. Compared with patients with mild or moderate OSA, patients with severe OSA had a persistently higher apnea–hypopnea index (mild 2.0±1.8, moderate 1.0±0.9, severe 5.8±5.6; P=0.015), perhaps explaining why the potassium channel changes were not seen in the severe OSA group.ConclusionsThe mRNA expression of most potassium channels inversely correlates with the severity of OSA and hypoxemia. Continuous positive airway pressure therapy improves circulating KCNQ1 and KCNJ2 in patients with moderate OSA.

show abstract

“…The newer more detailed classification scheme is based on the genetic mutation involved. Ten forms of congenital LQTS have been identified due to mutations in genes encoding for potassium channels, sodium channels or membrane components located on chromosome 3, 4, 6, 7, 11, 17 and 21 (Table 1) (Andersen et al, 1971;Tawil et al, 1994;Splawski et al, 2000;Plaster et al, 2001;Mohler et al, 2003;Splawski et al, 2004;Vatta et al, 2006;Medeiros-Domingo et al, 2007).…”

Section: Molecular Genetics Of Lqtsmentioning

confidence: 99%

“…It is noteworthy that causative mutations can be identified in approximately 75% of LQTS cases only, indicating additional genetic heterogeneity of the syndrome. LQT1 is the most common accounting for 30 to 35% of cases, followed by LQT2 (25-30% cases) and LQT3 (5 to 10% cases) (Splawski et al, 2000).…”

Section: Molecular Genetics Of Lqtsmentioning

confidence: 99%

Pharmacological approach to the treatment of long and short QT syndromes

Patel

Antzelevitch

2008

Pharmacology & Therapeutics

View full text Add to dashboard Cite

Inherited channelopathies have received increasing attention in recent years. The past decade has witnessed impressive progress in our understanding of the molecular and cellular basis of arrhythmogenesis associated with inherited channelopathies. An imbalance in ionic forces induced by these channelopathies affects the duration of ventricular repolarization and amplifies the intrinsic electrical heterogeneity of the myocardium, creating an arrhythmogenic milieu. Today, many of the channelopathies have been linked to mutations in specific genes encoding either components of ion channels or membrane or regulatory proteins. Many of the channelopathies are genetically heterogeneous with a variable degree of expression of the disease. Defining the molecular basis of channelopathies can have a profound impact on patient management, particularly in cases in which genotype-specific pharmacotherapy is available.The long QT syndrome (LQTS) is one of the first identified and most studied channelopathies where abnormal prolongation of ventricular repolarization predisposes an individual to life threatening ventricular arrhythmia called Torsade de Pointes. On the other hand of the spectrum, molecular defects favoring premature repolarization lead to Short QT syndrome (SQTS), a recently described inherited channelopathy. Both of these channelopathies are associated with a high risk of sudden cardiac death due to malignant ventricular arrhythmia. Whereas pharmacological therapy is first line treatment for LQTS, defibrillators are considered as primary treatment for SQTS. This review provides a comprehensive review of the molecular genetics, clinical features, genotype-phenotype correlations and genotype-specific approach to pharmacotherapy of these two mirror-image channelopathies, SQTS and LQTS.

show abstract

Spectrum of Mutations in Long-QT Syndrome Genes

Cited by 1,135 publications

References 77 publications

KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death

KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death

Obstructive Sleep Apnea and Circulating Potassium Channel Levels

Pharmacological approach to the treatment of long and short QT syndromes

Contact Info

Product

Resources

About