Long QT syndrome with compound mutations is associated with a more severe phenotype: A Japanese multicenter study

Itoh, Hideki; Shimizu, Wataru; Hayashi, Kenshi; Yamagata, Kenichiro; Sakaguchi, Tomoko; Ohno, Seiko; Makiyama, Takeru; Akao, Masaharu; Ai, Tomohiko; Noda, Takashi; Miyazaki, Aya; Miyamoto, Yoshihiro; Yamagishi, Masakazu; Kamakura, Shiro; Horie, Minoru

doi:10.1016/j.hrthm.2010.06.013

Cited by 103 publications

(79 citation statements)

References 28 publications

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“…44- 46 Compound mutations (ie, ≥2 mutations) are found in 10% of genotype-positive patients 47 and the clinical manifestation of disease in such patients is often more severe. 48, 49 As for minor LQTS subtypes with severe clinical phenotypes, mutations in KCNQ1 or KCNE1 present as homozygous or compound heterozygous mutations in Jervell and LangeNielsen syndrome (J-LNS; Table 2). 50,51 KCNQ1 mutations are much more prevalent (90%) than KCNE1 mutations (10%).…”

Section: Electrophysiological and Genetic Abnormalities In Lqtsmentioning

confidence: 99%

Genetic and Clinical Advances in Congenital Long QT Syndrome

Mizusawa

Horie

Wilde

2014

Circ J

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129

114

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Section: Electrophysiological and Genetic Abnormalities In Lqtsmentioning

confidence: 99%

Genetic and Clinical Advances in Congenital Long QT Syndrome

Mizusawa

Horie

Wilde

2014

Circ J

Self Cite

129

114

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“…13 Two genotypes, JLN1 and JLN2 are responsible for homozygous or compound heterozygous mutations in KCNQ1 and/or KCNE1, both of which are responsible for a decrease in the IKs ( Table 1); 4-11% of LQTS patients carries homozygous or compound heterozygous mutations in 2 LQTS-causing genes, and generally have a longer QTc and 3.5-fold more risk of cardiac arrest. 16 Several single mutations in SCN5A produce multiple phenotypes, such as BrS, sick sinus syndrome, and conduction disease, in addition to the LQT3 phenotype. 17 Genotype-phenotype correlations have been rigorously investigated over the past 2 decades as will be presented next.…”

Section: Genotype-phenotype Correlations In Congenital Lqtsmentioning

confidence: 99%

Update of Diagnosis and Management of Inherited Cardiac Arrhythmias

Shimizu

2013

Circ J

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“…In addition to these 3 genes, we examined the entire coding sequence of KCNQ1, KCNH2, SCN5A, and KCNE1-5 to exclude the unexpected presence of compound mutations related to primary electric diseases. 21,22 When a mutation was detected, we examined its presence in Ͼ200 Japanese control subjects to exclude the possibility of polymorphisms. When mutations were detected in probands, we also screened their family members.…”

Section: Dna Isolation and Mutation Analysismentioning

confidence: 99%

Phenotype Variability in Patients Carrying KCNJ2 Mutations

Kimura

Zhou

Kawamura

et al. 2012

Circ Cardiovasc Genet

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Background-Mutations of KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1, cause Andersen-Tawil syndrome (ATS), a disease exhibiting ventricular arrhythmia, periodic paralysis, and dysmorphic features. However, some KCNJ2 mutation carriers lack the ATS triad and sometimes share the phenotype of catecholaminergic polymorphic ventricular tachycardia (CPVT). We investigated clinical and biophysical characteristics of KCNJ2 mutation carriers with "atypical ATS." Methods and Results-Mutational analyses of KCNJ2 were performed in 57 unrelated probands showing typical (Ն2 ATS features) and atypical (only 1 of the ATS features or CPVT) ATS. We identified 24 mutation carriers. Mutation-positive rates were 75% (15/20) in typical ATS, 71% (5/7) in cardiac phenotype alone, 100% (2/2) in periodic paralysis, and 7% (2/28) in CPVT. We divided all carriers (nϭ45, including family members) into 2 groups: typical ATS (A) (nϭ21, 47%) and atypical phenotype (B) (nϭ24, 53%). Patients in (A) had a longer QUc interval [(A): 695Ϯ52 versus (B):643Ϯ35 ms] and higher U-wave amplitude (0.24Ϯ0.07 versus 0.18Ϯ0.08 mV). C-terminal mutations were more frequent in (A) (85% versus 38%, PϽ0.05). There were no significant differences in incidences of ventricular tachyarrhythmias. Functional analyses of 4 mutations found in (B) revealed that R82Q, R82W, and G144D exerted strong dominant negative suppression (current reduction by 95%, 97%, and 96%, respectively, versus WT at Ϫ50 mV) and T305S moderate suppression (reduction by 89%). Conclusions-KCNJ2 gene screening in atypical ATS phenotypes is of clinical importance because more than half of mutation carriers express atypical phenotypes, despite their arrhythmia severity. (Circ Cardiovasc Genet. 2012; 5:344-353.)

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Long QT syndrome with compound mutations is associated with a more severe phenotype: A Japanese multicenter study

Cited by 103 publications

References 28 publications

Genetic and Clinical Advances in Congenital Long QT Syndrome

Genetic and Clinical Advances in Congenital Long QT Syndrome

Update of Diagnosis and Management of Inherited Cardiac Arrhythmias

Phenotype Variability in Patients Carrying KCNJ2 Mutations

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