Genotype- and Phenotype-Guided Management of Congenital Long QT Syndrome

Giudicessi, John R.; Ackerman, Michael J.

doi:10.1016/j.cpcardiol.2013.08.001

Cited by 142 publications

(116 citation statements)

References 131 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…28 Although in our analysis the percentage of discordance was low, segregation analysis and/or functional studies are necessary to verify the pathogenicity or neutrality of these mutations. 28,37 Taking together, without validation, some of these mutations predicted as neutral or discordance will remain of uncertain significance, confounding genetic diagnosis.…”

Section: Pathogenicity Prediction With In Silico Toolsmentioning

confidence: 99%

Genetic analysis, in silico prediction, and family segregation in long QT syndrome

et al. 2014

View full text Add to dashboard Cite

The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTcZ500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality.

show abstract

Section: Pathogenicity Prediction With In Silico Toolsmentioning

confidence: 99%

Genetic analysis, in silico prediction, and family segregation in long QT syndrome

et al. 2014

View full text Add to dashboard Cite

show abstract

“…[23][24][25][26] Patients with a SCN5A mutation are well characterized, whereas those with mutations in CAV3, SCN4B, and SNTA1 less so, because they are very rare. 27 Because LQT3 is known for its high risk of fatal consequences caused by VF, confirmation of SCN5A mutation carriership is important for the prevention of future fatal arrhythmic events. Treatment with b-blockers is essential for patients with recurrent arrhythmic events, 28 although b-blockers are less effective than in LQT1 or LQT2.…”

Section: Long Qt Syndromementioning

confidence: 99%

Sodium Current Disorders

Mizusawa

Tan

2014

Cardiac Electrophysiology Clinics

View full text Add to dashboard Cite

“…According to a gene possessing mutations, LQTS has been classified into subtypes, of which LQT1, LQT2, and LQT3 are the most common. The first two types result from changes in the potassium channel genes KCNQ1 and KCNH2 (HERG), respectively, while LQT3 is caused by mutations in the gene SCN5A, encoding the sodium channel (Giudicessi & Ackerman, 2013b). The estimated prevalence of this disorder in Finland is 1:250 (Marjamaa et al, 2009), whereas in other populations it is reported to be 1:2000 (Schwartz et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Is Symptomatic Long QT Syndrome Associated with Depression in Women and Men?

Wesołowska

Elovainio

Koponen

et al. 2016

Journal of Genetic Counseling

View full text Add to dashboard Cite

We examined whether long QT syndrome (LQTS) mutation carrier status or symptomatic LQTS are associated with depression, and whether there are sex differences in these potential relationships.The sample comprised 782 participants (252 men). Of the 369 genetically defined LQTS mutation carriers, 169 were symptomatic and 200 were asymptomatic. The control group consisted of 413 unaffected relatives. Depression was assessed using the Beck Depression Inventory-II (BDI-II). No association was found for LQTS mutation carrier status with depression. The multinomial logistic regression showed that LQTS mutation carrier men with arrhythmic events scored higher on depression compared with the control group, even when adjusting for age, β-blockers, antidepressants, and social support (OR = 1.09, 95% CI [1.02, 1.15], p = .007). The binary logistic regression comparing symptomatic and asymptomatic LQTS mutation carriers showed that symptomatic LQTS was associated with depression in men (OR = 1.10, 95% CI [1.03, 1.19], p = .009). The results were unchanged when additionally adjusted for education. These findings suggest that symptomatic LQTS is associated with depression in men but not in women. Overall, however, depression is more frequent in women than men. Thus, regular screening for depression in LQTS mutation carriers and their unaffected family members can be important.

show abstract

Genotype- and Phenotype-Guided Management of Congenital Long QT Syndrome

Cited by 142 publications

References 131 publications

Genetic analysis, in silico prediction, and family segregation in long QT syndrome

Genetic analysis, in silico prediction, and family segregation in long QT syndrome

Sodium Current Disorders

Is Symptomatic Long QT Syndrome Associated with Depression in Women and Men?

Contact Info

Product

Resources

About