Next generation sequencing for clinical diagnostics and personalised medicine: implications for the next generation cardiologist

Ware, James S.; Roberts, Angharad; Cook, Stuart A.

doi:10.1136/heartjnl-2011-300742

Cited by 48 publications

(27 citation statements)

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“…Despite a strong genetic basis for DCM (2) and the recent advent of affordable and comprehensive exome and genome sequencing techniques that permit screening of all DCM genes (3–5), the application of clinical molecular diagnostics in DCM management remains limited (6), due to historically low mutational yield and a background of protein-altering variation of uncertain significance in the general population that make variant interpretation challenging (7–9). …”

Section: Introductionmentioning

confidence: 99%

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease

et al. 2015

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The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) provides new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5,267 individuals across the spectrum of cardiac physiology, and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms, and demonstrate that these data, coupled with TTNtv position, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause for DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses we provide evidence for a length-dependent, dominant negative mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.

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Section: Introductionmentioning

confidence: 99%

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease

et al. 2015

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“…Technological advances in the preparation of DNA before sequencing (enriching and labelling, for example), in sequencing chemistry and in bioinformatics will result in reduced costs and improvements in automation, accuracy and coverage. Recently published reviews describe NGS in more detail, and specifically with reference to inherited heart disease 86 87…”

Section: Geneticsmentioning

confidence: 99%

Almanac 2011: cardiomyopathies. The national society journals present selected research that has driven recent advances in clinical cardiology

Elliott

Mohiddin

2011

Heart

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“…Until recently the Sanger method has been the gold standard used for DNA sequencing [5]. However, the clinical phenotype in patients with inherited cardiac arrhythmias is not always evident.…”

Section: Introductionmentioning

confidence: 99%

Targeted next generation sequencing in a young population with suspected inherited malignant cardiac arrhythmias

et al. 2018

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Aborted sudden cardiac death in the young often is due to inherited heart disease. However, the clinical phenotype in these patients is not always evident. The aim of this study was to identify pathogenic molecular genetic variants in a population with suspected inherited cardiac arrhythmias. Eligible patients were admitted to Aarhus University Hospital, Denmark during the period 1999–2013 with arrhythmias assumed caused by a hereditary heart disease, and in whom no genotype had been established. We used the Danish national pacemaker and ICD registry to identify this cohort. One third (24/80) of the study population had first-line genetic testing with a targeted next-generation sequencing (NGS) panel, and two-third (56/80) of the study population had second-line genetic testing with NGS where prior Sanger sequencing did not reveal a causative variant. Variants were assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We included 80 patients. Median age (IQR) was 38 (28–43) years, 54 (68%) were males. First-line genetic testing identified a genetic variant in 33% (8/24) of the cases and second-line genetic testing revealed a variant in 20% (11/56) of the cases. Eleven variants were considered pathogenic, three likely pathogenic and 10 were variants of unknown significance (VUS). Seventeen variants were very rare with a minor allele frequency (MAF) ≤0.02% in all population databases used in the study. Molecular genetic testing of patients with suspected inherited cardiac arrhythmias with NGS identifies a molecular-genetic cause in a significant proportion of patients.

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Next generation sequencing for clinical diagnostics and personalised medicine: implications for the next generation cardiologist

Cited by 48 publications

References 50 publications

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease

Almanac 2011: cardiomyopathies. The national society journals present selected research that has driven recent advances in clinical cardiology

Targeted next generation sequencing in a young population with suspected inherited malignant cardiac arrhythmias

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