Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users’ views

Bertier, Gabrielle; Hetu, Martin; Joly, Yann

doi:10.1186/s12920-016-0213-6

Cited by 69 publications

(72 citation statements)

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“…Research across the ethical, legal and social spectrum reports best practices for engaging families in CGES, including providing pretest education, obtaining informed consent to prepare families for results and helping families make decisions about learning secondary findings [8–10]. Such secondary findings may include variants in genes for medically actionable Mendelian conditions, as well as other categories of findings including those related to nonmedically actionable genetic conditions, carrier status and pharmacogenetics results.…”

Section: Introductionmentioning

confidence: 99%

How Do Providers Discuss the Results of Pediatric Exome Sequencing with Families?

et al. 2017

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Aim This study provides preliminary data on the process and content of returning results from exome sequencing offered to children through one of the Clinical Sequencing Exploratory Research (CSER) projects. Materials & methods We recorded 25 sessions where providers returned diagnostic and secondary sequencing results to families. Data interpretation utilized inductive thematic analysis. Results Typically, providers followed a results report and discussed diagnostic findings using technical genomic and sequencing concepts. We identified four provider processes for returning results: teaching genetic concepts; assessing family response; personalizing findings; and strengthening patient–provider relationships. Conclusion Sessions should reflect family interest in medical management and next steps, and minimize detailed genomic concepts. As the scope and complexity of sequencing increase, the traditional information-laden counseling model requires revision.

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Section: Introductionmentioning

confidence: 99%

How Do Providers Discuss the Results of Pediatric Exome Sequencing with Families?

et al. 2017

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“…Increases in our understanding of rare variants have now advanced –– via whole-exome sequencing (WES) (Bertier, Hetu, & Joly, 2016) and whole-genome sequencing (WGS); also called “next-generation” sequencing (NGS) (Cirulli & Goldstein, 2010; Pinto, Ariani, Bianciardi, Daga, & Renieri, 2016). …”

Section: Brief History Of Geneticsmentioning

confidence: 99%

Personalized medicine: Genetic risk prediction of drug response

Zhang

Nebert

2017

Pharmacology & Therapeutics

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Pharmacogenomics (PGx), a substantial component of “personalized medicine”, seeks to understand each individual's genetic composition to optimize drug therapy reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants. [b] Predominantly oligogenic traits represent variation largely influenced by a small number of major pharmacokinetic or pharmacodynamic genes. [c] Complex PGx traits resemble most multifactorial quantitative traits –– influenced by numerous small-effect variants, together with epigenetic effects and environmental factors. Prediction of monogenic drug responses is relatively simple, involving detection of underlying mutations; due to rarity of these events and incomplete penetrance, however, prospective tests based on genotype will have high false-positive rates, plus pharmacoeconomics will require justification. Prediction of predominantly oligogenic traits is slowly improving. Although a substantial fraction of variation can be explained by limited numbers of large-effect genetic variants, uncertainty in successful predictions and overall cost-benefit ratios will make such tests elusive for everyday clinical use. Prediction of complex PGx traits is almost impossible in the foreseeable future. Genome-wide association studies of large cohorts will continue to discover relevant genetic variants; however, these small-effect variants, combined, explain only a small fraction of phenotypic variance –– thus having limited predictive power and clinical utility.

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“…In addition, despite being a promising tool, the WES method is still under development. For this reason, WES still poses challenges regarding the establishement of a standard method for data analysis and for the interpretation of the results [52]. Consequently, the combination of other bioinformatics techniques [53,54], including data from prior GWAS studies, may still be needed for identifying causative mutations.…”

Section: Discussionmentioning

confidence: 99%

Single Nucleotide Variants in A Family of Monozygotic Twins Discordant for the Phenotype Congenital Megaureter: A Genomic Analysis

Santos¹,

Rodrigues²,

Cardenas³

et al. 2017

TOUNJ

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Introduction:Congenital megaureter constitutes the second most frequent cause of hydronephrosis in children. There is still much debate on what extent environmental or genetic factors are involved in the pathogenesis of congenital megaureter. Objectives:This study aimed at investigating a pair of monozygotic twins discordant for the expression of bilateral congenital megaureter using the whole exome sequencing technique. Methods:Peripheral blood DNA was extracted and then sequenced using the whole exome technique from a pair of twins discordant for the presence of bilateral congenital refluxing unobstructed megaureter, his parents and a set of 11 non-related individuals with confirmed diagnosis of congenital megaureter. The DNA of the set of 11 non-related individuals was pooled in three groups. The monozygotic twins and their parents had DNA samples sequenced separately. Sanger validation was performed after data was filtered. Results:In the proband were identified 256 candidate genes, including TBX3, GATA6, DHH, LDB3, and HNF1, which are expressed in the urinary tract during the embryonic period. After Sanger validation, the SNVs found in the genes TBX3, GATA6, DHH and LDB3 were not confirmed in the proband. The SNV chr17:36104650 in the HNF1b gene was confirmed in the proband, his twin brother and the mother, however was not found in the pool of 11 non-related individuals with congenital megaureter. Conclusion:Due to the possible complex causative network of genetic variations and the challenges regarding the use of the whole exome sequencing technique we could not unequivocally associate the genetic variations identified in this study with the development of the congenital megaureter.

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Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users’ views

Cited by 69 publications

References 100 publications

How Do Providers Discuss the Results of Pediatric Exome Sequencing with Families?

How Do Providers Discuss the Results of Pediatric Exome Sequencing with Families?

Personalized medicine: Genetic risk prediction of drug response

Single Nucleotide Variants in A Family of Monozygotic Twins Discordant for the Phenotype Congenital Megaureter: A Genomic Analysis

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