Junichi Ozawa

Pediatric Cohort With Long QT Syndrome – KCNH2 Mutation Carriers Present Late Onset But Severe Symptoms –

BACKGROUND In children with long QT syndrome (LQTS), risk factors for cardiac events have been reported, but age-, gender- and genotype-related differences in prognosis remain unknown in Asian countries. METHODSANDRESULTS The study examined clinical prognosis at age between 1 and 20 years in 496 LQTS patients who were genotyped as either of LQT1-3 (male, n=206). Heterozygous mutations were observed in 3 major responsible genes:KCNQ1in271,KCNH2in 192, andSCN5Ain 33 patients. LQTS-associated events were classified into 3 categories: (1) syncope (n=133); (2) repetitive torsade de pointes (TdP, n=3); and (3) cardiopulmonary arrest (CPA, n=4). The risk of cardiac events was significantly lower in LQT1 girls than boys≤12 years (HR, 0.55), whereas LQT2 female patients ≥13 years had the higher risk of cardiac events than male patients (HR, 4.60). Patients in the repetitive TdP or CPA group included 1 LQT1 female patient, 1 LQT2 male patient, and 5 LQT2 female patients. All LQT2 patients in these groups had TdP repeatedly immediately after the antecedent event. In addition, all 5 female LQT2 patients in these groups had the event after or near puberty. CONCLUSIONS Female LQT2 children might have repeated TdP shortly after prior events, especially after puberty. (Circ J 2016; 80: 696-702).

Copy number variations of SCN5A in Brugada syndrome

BACKGROUND Loss-of-function mutations in SCN5A are associated in ∼20% of Brugada syndrome (BrS) patients. Copy number variations (CNVs) have been shown to be associated with several inherited arrhythmia syndromes. OBJECTIVE The purpose of this study was to investigate SCN5A CNVs among BrS probands. METHODS The study cohort consisted of 151 BrS probands who were symptomatic or had a family history of BrS, sudden death, syncope, or arrhythmic diseases. We performed sequence analysis of SCN5A by the Sanger method. For detecting CNVs in SCN5A, we performed multiplex ligation-dependent probe amplification analysis of the 151 BrS probands. RESULTS We identified pathogenic SCN5A mutations in 20 probands by the Sanger method. In 140 probands in whom multiplex ligation-dependent probe amplification was successfully performed, 4 probands were found to present different CNVs (deletion in 3 and duplication in 1). Three of them had fatal arrhythmia events; the remaining 1 was asymptomatic but had a family history. Mean age at diagnosis was 23 ± 14 years. All of the baseline 12-lead electrocardiograms showed PQ-interval prolongation. The characteristics of these 4 probands with CNVs were similar to those of the probands with mutations leading to premature truncation of the protein or missense mutations causing peak INa reduction >90%. CONCLUSION We identified SCN5A CNVs in 2.9% of BrS probands who were symptomatic or had a family history.

Short QT syndrome in a boy diagnosed on screening for heart disease

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.

A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects

Key Teaching Points • Electrocardiograms in patients with Timothy syndrome patients sometimes present T-wave depolarization pattern similar to long QT syndrome type 3, such as a late-onset peaked T wave. • We identified a novel CACNA1C mutation, S643F, in a 14-year-old boy with Timothy syndrome without syndactyly. • S643F is located within the Cav1.2 S4–S5 linker of domain II, and the mutant channel exerts both marked loss-of function and gain-of-function effects.

SCN5A mutations in 442 neonates and children: genotype–phenotype correlation and identification of higher-risk subgroups

Aims To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. Conclusion In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.

Multigenerational Inheritance of Long QT Syndrome Type 2 in a Japanese Family.

Congenital long QT syndrome (LQTS) is an important cause of sudden cardiac death in young people without any other structural disease. Mutations in the genes encoding the cardiac ion channels or associated proteins have been shown to result in ion channel dysfunction and thereby causing LQTS. We investigated a Japanese family with LQTS for four generations, with the female family members showing severe symptoms. We performed genetic tests for LQTS-related genes and identified a heterozygous KCNH2 mutation (p.K638del). In the family, the KCNH2 mutation had a very high multigenerational inheritance, and female genotype positives showed more severe phenotypes.