Compound and heterozygous mutations of
            KCNQ1
            in long QT syndrome with familial history of unexplained sudden death: Identified by analysis of whole exome sequencing and predisposing genes

Long QT syndrome (LQTS), which is caused by an ion channel‐related gene mutation, is a malignant heart disease with a clinical course of a high incidence of ventricular fibrillation and sudden cardiac death in the young. Mutations in KCNH2 (which encodes potassium voltage-gated channel subfamily H member 2) are responsible for LQTS in many patients. Here we report the novel mutation c.1898A>C in KCNH2 in a Chinese family with LQTS through whole-exome sequencing. The c.916dupA mutation in JUP (which encodes junction plakoglobin) is also discovered. Mutations in JUP were found to be associated with arrhythmogenic right ventricular cardiomyopathy. The double mutation in the proband may help explain his severe clinical manifestations, such as sudden cardiac death at an early age. Sequencing for the proband’s family members revealed that the KCNH2 mutation descends from his paternal line, while the mutation in JUP came from his maternal line. The data provided in this study may help expand the spectrum of LQTS-related KCNH2 mutations and add support to the genetic diagnosis and counseling of families affected by malignant arrhythmias.

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ECG patterns related to arrhythmias and sudden death: channelopathies, early repolarization, and pre-excitation

ESC CardioMed ◽

10.1093/med/9780198784906.003.0074 ◽

2018 ◽

pp. 382-389

Author(s):

Wojciech Zareba ◽

Pyotr Platonov

Keyword(s):

Sudden Death ◽

Long Qt Syndrome ◽

Ventricular Arrhythmias ◽

Prior History ◽

Long Qt ◽

Early Repolarization ◽

Genes Encoding ◽

History Of ◽

Qt Syndrome ◽

Characteristic Features

Electrocardiogram (ECG) patterns recognized in patients with sudden death without structural abnormalities in the heart have guided cardiology over the last few decades towards a better understanding of the role of cardiac ion channels in physiology and in arrhythmogenicity in rare electrical diseases. The long QT syndrome became the paradigm for evaluating the association between specific ion channel abnormalities caused by mutations in genes encoding predominantly potassium and sodium channels and phenotypic ECG expression. Specific ECG patterns observed in long QT syndrome help in diagnosis and improve prognosis in patients affected by this disorder. Short QT syndrome also is characterized by specific patterns in repolarization morphology that relate to affected potassium current or calcium handling genes. Brugada syndrome and early repolarization syndrome are considered as J-wave syndromes, having some similarities in ECG features but with distinctive patterns associated with classical forms of these disorders. Spontaneous appearance of cove-type Brugada pattern is associated with a worse prognosis. Early repolarization patterns may also indicate prognosis in subjects with a prior history of cardiac arrest or ventricular arrhythmias or a family history of cardiac arrests. Catecholaminergic polymorphic ventricular tachycardia is another channelopathy without characteristic features in standard resting ECG but with characteristic polymorphic ventricular arrhythmias during catecholaminergic challenge (exercise test, stressing situations). Pre-excitation syndromes associated with sudden cardiac death are well recognized and current understanding of these disorders leads to a better therapy.

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Amino acid–level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise

Heart Rhythm ◽

10.1016/j.hrthm.2018.02.031 ◽

2018 ◽

Vol 15 (7) ◽

pp. 1042-1050 ◽

Cited By ~ 4

Author(s):

Andrew P. Landstrom ◽

Ernesto Fernandez ◽

Jill A. Rosenfeld ◽

Yaping Yang ◽

Andrew L. Dailey-Schwartz ◽

...

Keyword(s):

Amino Acid ◽

Exome Sequencing ◽

Long Qt Syndrome ◽

Acid Level ◽

Noise Analysis ◽

Amino Acid Level ◽

Signal To Noise ◽

Long Qt ◽

Whole Exome ◽

Qt Syndrome

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A rare indication of permanent pacemaker implantation in children: congenital long QT syndrome

Cardiology in the Young ◽

10.1017/s1047951120003108 ◽

2020 ◽

Vol 30 (12) ◽

pp. 1880-1881

Author(s):

Mehmet Taşar ◽

Nur Dikmen Yaman ◽

Huseyin Dursin ◽

Murat Şimşek ◽

Senem Özgür

Keyword(s):

Sudden Death ◽

Long Qt Syndrome ◽

Pacemaker Implantation ◽

Torsades De Pointes ◽

Permanent Pacemaker ◽

Long Qt ◽

Permanent Pacemaker Implantation ◽

Qt Syndrome ◽

Congenital Lqts ◽

Congenital Long Qt Syndrome

AbstractCongenital Long QT Syndrome (LQTS) is a dangerous arrhythmic disorder that can be diagnosed in children with bradycardia. It is characterised by a prolonged QT interval and torsades de pointes that may cause sudden death. Long QT syndrome is an ion channelopathy with complex molecular and physiological infrastructure. Unlike the acquired type, congenital LQTS has a genetic inheritance and it may be diagnosed by syncope, stress in activity, cardiac dysfunction, sudden death or sometimes incidentally. Permanent pacemaker implantation is required for LQTS with resistant bradycardia even in children to resolve symptoms and avoid sudden death.

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GW28-e1209 Whole Exome Sequencing Identified a Pathogenic Mutation in RYR2 in a Chinese Family with Unexplained Sudden Death

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2017.07.166 ◽

2017 ◽

Vol 70 (16) ◽

pp. C49

Author(s):

Yubi Lin ◽

Zili Liao ◽

Siqi He ◽

Ruilin Liu ◽

Yongzheng Peng ◽

...

Keyword(s):

Sudden Death ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Pathogenic Mutation ◽

Chinese Family ◽

Whole Exome

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A SCN5A mutation caused ST elevation, transient QT prolongation and sudden death: An atypical phenotype of Brugada-long QT syndrome?

Heart Rhythm ◽

10.1016/j.hrthm.2005.02.833 ◽

2005 ◽

Vol 2 (5) ◽

pp. S265

Author(s):

Li Zhang ◽

Tiehua Chen ◽

Michael Sheets ◽

Robert L. Lux ◽

Michael S. Schaffer ◽

...

Keyword(s):

Sudden Death ◽

Long Qt Syndrome ◽

Qt Prolongation ◽

Long Qt ◽

St Elevation ◽

Qt Syndrome ◽

Atypical Phenotype ◽

Scn5a Mutation

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Paediatric/young versus adult patients with long QT syndrome

Open Heart ◽

10.1136/openhrt-2021-001671 ◽

2021 ◽

Vol 8 (2) ◽

pp. e001671

Author(s):

Sharen Lee ◽

Jiandong Zhou ◽

Kamalan Jeevaratnam ◽

Wing Tak Wong ◽

Ian Chi Kei Wong ◽

...

Keyword(s):

Long Qt Syndrome ◽

Primary Outcome ◽

Population Based ◽

Public Hospitals ◽

Qtc Interval ◽

Onset Age ◽

Long Qt ◽

History Of ◽

Qt Syndrome ◽

Random Survival Forest

IntroductionLong QT syndrome (LQTS) is a less prevalent cardiac ion channelopathy than Brugada syndrome in Asia. The present study compared the outcomes between paediatric/young and adult LQTS patients.MethodsThis was a population-based retrospective cohort study of consecutive patients diagnosed with LQTS attending public hospitals in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF).ResultsA total of 142 LQTS (mean onset age=27±23 years old) were included. Arrhythmias other than VT/VF (HR 4.67, 95% CI (1.53 to 14.3), p=0.007), initial VT/VF (HR=3.25 (95% CI 1.29 to 8.16), p=0.012) and Schwartz score (HR=1.90 (95% CI 1.11 to 3.26), p=0.020) were predictive of the primary outcome for the overall cohort, while arrhythmias other than VT/VF (HR=5.41 (95% CI 1.36 to 21.4), p=0.016) and Schwartz score (HR=4.67 (95% CI 1.48 to 14.7), p=0.009) were predictive for the adult subgroup (>25 years old; n=58). A random survival forest model identified initial VT/VF, Schwartz score, initial QTc interval, family history of LQTS, initially asymptomatic and arrhythmias other than VT/VF as the most important variables for risk prediction.ConclusionClinical and ECG presentation varies between the paediatric/young and adult LQTS population. Machine learning models achieved more accurate VT/VF prediction.

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