Long QT syndrome, cardiovascular anomaly and findings in ECG-guided genetic testing

Al-Senaidi, Khalfan S.; Wang, Guoliang; Zhang, Li; Beer, Dominik; Al-Farqani, Abdullah; AlMaskaryi, Salim N.; Penny, Daniel J.; Kowey, Peter R.; Fan, Yuxin

doi:10.1016/j.ijchv.2014.06.001

Cited by 6 publications

(10 citation statements)

References 34 publications

(48 reference statements)

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“…In recent years, with the emerging technology of next-generation sequencing, there is a tendency to perform genome-wide gene hunting in LQTS, which, in turn, further boosts the cost of genotyping. In our study, 92% (172/186) of LQTS patients with genotype-positive results were single-gene mutation carriers [20] of KCNQ1 , KCNH2 and SCN5A . This indicates that screening rare genes or conducting genome-wide screening is perhaps unnecessary in most cases.…”

Section: Discussionmentioning

confidence: 81%

Common Genotypes of Long QT Syndrome in China and the Role of ECG Prediction

Gao¹,

Liu²,

Li³

et al. 2015

Cardiology

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Objectives: Genetic testing, a gold standard for long QT syndrome (LQTS) diagnosis, is time-consuming and costly when all the 15 candidate genes are screened. Since genotype-specific ECG patterns are present in most LQT1-3 mutation carriers, we tested the utility of ECG-guided genotyping in a large cohort of Chinese LQTS patients. Methods and Results: We enrolled 230 patients (26 ± 17 years, 66% female) with a clinical diagnosis of LQTS. Genotypes were predicted as LQT1-3 based on the presence of ECG patterns typical for each genotype in 200 patients (85 LQT1, 110 LQT2 and 5 LQT3). Family-based genotype prediction was also conducted if gene-specific ECG patterns were found in other affected family members. Mutational screening identified 104 mutations (44% novel), i.e. 46 KCNQ1, 54 KCNH2 and 4 SCN5A mutations. The overall predictive accuracy of ECG-guided genotyping was 79% (157/200) and 79% (67/85), 78% (86/110) and 80% (4/5) for LQT1, LQT2 and LQT3, respectively. The predictive accuracy was 98% (42/43) when family-based ECG assessment was performed. Conclusions: From this large-scale genotyping study, we found that LQT2 is the most common genotype among the Chinese. Family-based ECG-guided genotyping is highly accurate. ECG-guided genotyping is time- and cost-effective. We therefore recommend it as an optimal approach for the genetic diagnosis of LQTS.

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Section: Discussionmentioning

confidence: 81%

Common Genotypes of Long QT Syndrome in China and the Role of ECG Prediction

Gao¹,

Liu²,

Li³

et al. 2015

Cardiology

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“…However, we were unable to make a definitive diagnosis because a QT prolongation was not proven. Through systematic literature review, we identified several additional cases of KCNH2 mutation with LVNC-LQTS combined phenotype (AlSenaidi et al, 2014;Ogawa et al, 2009;Rammes et al, 2017). The first association between LVNC and KCNH2 mutations was described by Ogawa et al (2009) reporting 2 unrelated individuals with isolated LVNC and LQTS carrying missense mutations in KCNH2.…”

Section: Discussionmentioning

confidence: 99%

“…The first association between LVNC and KCNH2 mutations was described by Ogawa et al (2009 ) reporting 2 unrelated individuals with isolated LVNC and LQTS carrying missense mutations in KCNH2. Subsequent AlSenaidi et al (2014 ) reported a 5-year-old girl of consanguineous Oman parents carrying a KCNH2 homozygous frameshift mutation in association with phenotypes including LVNC, dilated ascending aorta and LQTS. Interestingly, both the parents of the girl carried this KCNH2 heterozygous mutation but neither presented with LVNC, indicating that LVNC is incomplete in LQTS patients with KCNH2 mutations.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Biventricular Noncompaction Cardiomyopathy With Pulmonary Stenosis and Bradycardia in a Fetus With KCNH2 Mutation

et al. 2022

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Background: Left ventricular noncompaction (LVNC) is a rare cardiomyopathy, long QT syndrome (LQTS) is a rare ion channel disease, and simultaneous occurrence of both is even rarer. Further clinical reports and studies are needed to identify the association between LVNC and LQTS and the underlying mechanism.Methods and Results: A 26-year-old primigravida was referred at 25 weeks gestation for prenatal echocardiography due to fetal bradycardia detected during the routine ultrasound examination. The echocardiographic findings were consistent with biventricular noncompaction cardiomyopathy (BVNC) with pulmonary stenosis and suspected LQTS. After detailed counseling, the couple decided to terminate the pregnancy, and subsequent postmortem examination confirmed BVNC and pulmonary stenosis. Then, A trio (fetus and the parents) whole-exome sequencing (WES) and copy number variation sequencing (CNV-seq) were performed. CNV-seq identified no aneuploidy or pathogenic CNV. A de novo missense variant in KCNH2 (NM_000238.3:c.1847A > G,p.Tyr616Cys) was identified by WES. This KCNH2 missense mutation was classified as pathogenic according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant interpretation guidelines.Conclusion: We report the first prenatal case of KCNH2 mutation presenting with LVNC combined with bradycardia and second-degree 2:1 atrioventricular block. Importantly, this case reminds clinicians to systematically search ion channel gene mutations in patients with LVNC and arrhythmia.

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“…The genetic heterogeneity in long QT 3 and Brugada syndromes 4 has made this new genetic testing approach mandatory. The advantages of NGS versus the SSM in cases of genetic heterogeneity are undeniable, but NGS is still expensive and unaffordable for developing countries.…”

Section: Next-generation Sequencing: Available For Everyone?mentioning

confidence: 99%

Sanger sequencing as a first-line approach for molecular diagnosis of Andersen-Tawil syndrome

2017

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In 1977, Frederick Sanger developed a new method for DNA sequencing based on the chain termination method, now known as the Sanger sequencing method (SSM). Recently, massive parallel sequencing, better known as next-generation sequencing (NGS), is replacing the SSM for detecting mutations in cardiovascular diseases with a genetic background. The present opinion article wants to remark that “targeted” SSM is still effective as a first-line approach for the molecular diagnosis of some specific conditions, as is the case for Andersen-Tawil syndrome (ATS). ATS is described as a rare multisystemic autosomal dominant channelopathy syndrome caused mainly by a heterozygous mutation in the KCNJ2 gene . KCJN2 has particular characteristics that make it attractive for “directed” SSM. KCNJ2 has a sequence of 17,510 base pairs (bp), and a short coding region with two exons (exon 1=166 bp and exon 2=5220 bp), half of the mutations are located in the C-terminal cytosolic domain, a mutational hotspot has been described in residue Arg218, and this gene explains the phenotype in 60% of ATS cases that fulfill all the clinical criteria of the disease. In order to increase the diagnosis of ATS we urge cardiologists to search for facial and muscular abnormalities in subjects with frequent ventricular arrhythmias (especially bigeminy) and prominent U waves on the electrocardiogram.

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Long QT syndrome, cardiovascular anomaly and findings in ECG-guided genetic testing

Cited by 6 publications

References 34 publications

Common Genotypes of Long QT Syndrome in China and the Role of ECG Prediction

Common Genotypes of Long QT Syndrome in China and the Role of ECG Prediction

Case Report: Biventricular Noncompaction Cardiomyopathy With Pulmonary Stenosis and Bradycardia in a Fetus With KCNH2 Mutation

Sanger sequencing as a first-line approach for molecular diagnosis of Andersen-Tawil syndrome

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