The Promise and Challenges of Next-Generation Genome Sequencing for Clinical Care

Taber, Katherine Johansen; Dickinson, Barry D.; Wilson, Modena H.

doi:10.1001/jamainternmed.2013.12048

Cited by 147 publications

(73 citation statements)

References 42 publications

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“…To facilitate the interpretation of human genomic variants (31,32), we integrated the functional consequences of different computational methods, allele frequencies, and other genetic and clinical information related to all possible coding variants into a database, referred to as VarCards (33). However, it is unclear how the performances of these computational methods vary under different conditions.…”

Section: Introductionmentioning

confidence: 99%

Performance evaluation of pathogenicity-computation methods for missense variants

Zhao

Zhang

et al. 2018

Nucleic Acids Research

181

143

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With expanding applications of next-generation sequencing in medical genetics, increasing computational methods are being developed to predict the pathogenicity of missense variants. Selecting optimal methods can accelerate the identification of candidate genes. However, the performances of different computational methods under various conditions have not been completely evaluated. Here, we compared 12 performance measures of 23 methods based on three independent benchmark datasets: (i) clinical variants from the ClinVar database related to genetic diseases, (ii) somatic variants from the IARC TP53 and ICGC databases related to human cancers and (iii) experimentally evaluated PPARG variants. Some methods showed different performances under different conditions, suggesting that they were not always applicable for different conditions. Furthermore, the specificities were lower than the sensitivities for most methods (especially, for the experimentally evaluated benchmark datasets), suggesting that more rigorous cutoff values are necessary to distinguish pathogenic variants. Furthermore, REVEL, VEST3 and the combination of both methods (i.e. ReVe) showed the best overall performances with all the benchmark data. Finally, we evaluated the performances of these methods with de novo mutations, finding that ReVe consistently showed the best performance. We have summarized the performances of different methods under various conditions, providing tentative guidance for optimal tool selection.

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Section: Introductionmentioning

confidence: 99%

Performance evaluation of pathogenicity-computation methods for missense variants

Zhao

Zhang

et al. 2018

Nucleic Acids Research

181

143

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“…Although exome sequencing has been shown to be very promising as a diagnostic tool, there are still challenges for its widespread implementation in the routine clinical laboratory. Quite apart from the infrastructure required to support exome sequencing testing in the routine laboratory situation, one must also acquire the capability to analyze the data and interpret the results so as to determine the pathogenicity or otherwise of new (i.e., previously unreported) protein-altering variants detected in known disease genes [76]. …”

Section: Diagnostic Applicationsmentioning

confidence: 99%

The Rise and Rise of Exome Sequencing

Cooper

Patrinos

2016

Public Health Genomics

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Beginning in 2009, the advent of exome sequencing has contributed significantly towards new discoveries of heritable germline mutations and de novo mutations for rare Mendelian disorders with hitherto unknown genetic aetiologies. Exome sequencing is an efficient tool to identify disease mutations without the need of a multi-generational pedigree. Sequencing a single proband or multiple affected individuals has been shown to be successful in identifying disease mutations, but parents would be required in the case of de novo mutations. In addition to heritable germline and de novo mutations, exome sequencing has also succeeded in unravelling somatic driver mutations for a wide range of cancers through individual studies or international collaborative effort such as the Cancer Genome International Consortium. By contrast, the application of exome sequencing in complex diseases is relatively limited; probably it would be too expensive were it applied to thousands of samples to achieve the statistical power for rare or low frequency variants (<1%). On top of research discoveries, the application of exome sequencing as a diagnostic tool is also increasingly evident. In this article, we summarize and discuss the progress that has been made in these areas during almost a decade.

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“…Whole exome sequencing (WES) has proved to be useful across a variety of genetic disorders, simplifying the odyssey of many patients and their families and leading to subsequent changes in clinical management in a proportion of them (Johansen Taber, Dickinson & Wilson, 2014). Although a diagnostic yield of about 30% in neurogenetic disorders can be extrapolated from the results of large series that have included other medical conditions as well (Fogel et al, 2014;Gillissen et al, 2014;Bettencourt et al, 2014;Mercimek-Mahmutoglu et al, 2015), there are not specific reports assessing its utility in a setting such as ours: a neurogeneticist led academic group serving in a low-income country.…”

Section: Introductionmentioning

confidence: 99%

Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

Córdoba

Rodríguez-Quiroga

Vega

et al. 2016

Preprint

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Clinical variability is a hallmark of neurogenetic disorders. They involve widespread neurological entities such as neuropathies, ataxias, myopathies, mitochondrial encephalopathies, leukodystrophies, epilepsy and intellectual disabilities. Despite the use of considerable time and resources, the diagnostic yield in this field has been disappointingly low. This etiologic search has been called a "diagnostic odyssey" for many families. Whole exome sequencing (WES) has proved to be useful across a variety of genetic disorders, simplifying the odyssey of many patients and their families and leading to subsequent changes in clinical management in a proportion of them. Although a diagnostic yield of about 30% in neurogenetic disorders can be extrapolated from the results of large series that have included other medical conditions as well, there are not specific reports assessing its utility in a setting such as ours: a neurogeneticist led academic group serving in a low-income country.Herein, we report on a series of our first 40 consecutive cases that were selected for WES in a research-based neurogenetics laboratory. We demonstrated the clinical utility of WES in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%), describing cases in which clinical management was altered, and suggesting the potential cost-effectiveness of WES as a single test by examining the number and types of tests that were performed prior to

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The Promise and Challenges of Next-Generation Genome Sequencing for Clinical Care

Cited by 147 publications

References 42 publications

Performance evaluation of pathogenicity-computation methods for missense variants

Performance evaluation of pathogenicity-computation methods for missense variants

The Rise and Rise of Exome Sequencing

Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

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