D85N, a KCNE1 Polymorphism, Is a Disease-Causing Gene Variant in Long QT Syndrome

Nishio, Yoshihiko; Makiyama, Takeru; Itoh, Hideki; Sakaguchi, Tomoko; Ohno, Seiko; Gong, Yin-Zhi; Yamamoto, Satoshi; Ozawa, Tomoya; Ding, Wei‐Guang; Toyoda, Futoshi; Kawamura, Masataka; Akao, Masaharu; Matsuura, Hiroshi; Kimura, Takeshi; Kita, Toru; Horie, Minoru

doi:10.1016/j.jacc.2009.06.005

Cited by 149 publications

(154 citation statements)

References 29 publications

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“…Although this mutation is found in o1% of the general population, it has been described as an LQTS modulator 31,32 and associated with a QT prolongation. 33 Similarly, KCNE2 p.(Thr8Ala) was found in 0.5% of the general population but was also described as a VUS.…”

Section: Mutation Analysismentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Mutation Analysismentioning

confidence: 99%

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

et al. 2014

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“…1,13,26 Such intrafamilial variability in clinical phenotype indicates the significant role of modifying and triggering factors. 27 Common genetic variants (polymorphisms) have long been postulated to act as modifiers of clinical phenotype. To address this issue, Duchatelet et al 28 recently investigated a cohort from France, Italy and Japan including 112 duos (1 with cardiac events and 1 asymptomatic and untreated) of patients with known heterozygous LQT1 or LQT2 mutations.…”

Section: Polymorphism As a Modifier For Arrhythmic Risk In Congenitalmentioning

confidence: 99%

Update of Diagnosis and Management of Inherited Cardiac Arrhythmias

Shimizu

2013

Circ J

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“…Among the single-nucleotide polymorphisms involved in potassium channel diseases, KCNE1 D85N is well known not only as a modifier but also as a causative variant of LQTS. 30,123 In contrast, copy-number variations contain relatively large regions of the genome (kilobases to several megabases), with deletion (fewer than the normal number) or duplication (more than the normal number) on a certain chromosome, thereby giving the genome diversity. Recently, several copy-number variations in KCNH2 and KCNQ1 have been shown to be associated with disease.…”

Section: Diverse Mechanisms Underlie the Generation Of Cardiac Potassmentioning

confidence: 99%

Phenotypic Manifestations of Mutations in Genes Encoding Subunits of Cardiac Potassium Channels

Shimizu

Horie

2011

Circulation Research

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Abstract:Since 1995, when a potassium channel gene, hERG (human ether-à-go-go-related gene), now referred to as KCNH2, encoding the rapid component of cardiac delayed rectifier potassium channels was identified as being responsible for type 2 congenital long-QT syndrome, a number of potassium channel genes have been shown to cause different types of inherited cardiac arrhythmia syndromes. These include congenital long-QT syndrome, short-QT syndrome, Brugada syndrome, early repolarization syndrome, and familial atrial fibrillation. Genotype-phenotype correlations have been investigated in some inherited arrhythmia syndromes, and as a result, gene-specific risk stratification and gene-specific therapy and management have become available, particularly for patients with congenital long-QT syndrome. In this review article, the molecular structure and function of potassium channels, the clinical phenotype due to potassium channel gene mutations, including genotype-phenotype correlations, and the diverse mechanisms underlying the potassium channel gene-related diseases will be discussed. (Circ Res. 2011;109:97-109.)

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D85N, a KCNE1 Polymorphism, Is a Disease-Causing Gene Variant in Long QT Syndrome

Cited by 149 publications

References 29 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

Update of Diagnosis and Management of Inherited Cardiac Arrhythmias

Phenotypic Manifestations of Mutations in Genes Encoding Subunits of Cardiac Potassium Channels

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