Genome-Scale Sequencing in Clinical Care

Berg, Jonathan S.

doi:10.1001/jama.2014.14665

Cited by 22 publications

(13 citation statements)

References 10 publications

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“…Although those outcomes (including psychosocial) may vary, they can and must be measured, in DSD practice as in the case of any other chronic condition. 52 This effort should allow production of evidence for the efficacy of various methods toward an accurate diagnosis and, most importantly, the effects of a reliable diagnosis on evolving health-related quality-of-life outcomes for patients and families living with DSDs.…”

Section: Discussionmentioning

confidence: 99%

Genetics of Disorders of Sex Development

Sandberg¹,

Délot

Fox³

et al. 2017

Endocrinology and Metabolism Clinics of North America

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The Disorders of Sex Development (DSD) Consensus Conference, held in Chicago in 2005, identified several domains of care where improvement was needed.1 In particular, it called for the establishment of an infrastructure for collaborative interdisciplinary clinical practice and research, with the goal of integrating scientific understanding of DSD with real-time standardization and improvement in clinical practice. The DSD-Translational Research Network (DSD-TRN) was created in response, the first such North American infrastructure, a network of 4 (now expanded to 10) research and clinical sites and a central registry, with the collaboration of Accord Alliance, a nonprofit convener of diverse DSD stakeholders. To address the variability within and across medical, surgical, and behavioral health aspects of care, the DSD-TRN is dedicated to the standardization of diagnostic and treatment protocols in order to enhance clinical and scientific discovery, as well as quality of life outcomes for patients and their families. A critical aspect of this standardization of practice is a commitment to an early and comprehensive diagnostic process (including genetic), associated with extensive standardized phenotyping and psychosocial screening and support of patients and families. A recent review of the state of clinical, biochemical, genetic, and psychosocial evaluations of the newborn or adolescent with DSD, 10 years after the consensus statement, continued to highlight the need for a thorough diagnostic process that sets in motion informed discussions with parents (and newly diagnosed adolescent patients) regarding treatment options.2 Developmental pathways of sex determination and differentiation impacted in isolated and syndromic DSD conditions were recently reviewed.3–5 This article will briefly review the main categories of genetic causes of DSD and the diagnostic revolution promised by the advent of new genomic technology, and will present the DSD-TRN guidelines for genetic diagnosis, features of the registry for future research, and a peek into some early registry data.

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Section: Discussionmentioning

confidence: 99%

Genetics of Disorders of Sex Development

Sandberg¹,

Délot

Fox³

et al. 2017

Endocrinology and Metabolism Clinics of North America

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“…Since most known Mendelian disorders are associated with mutations in the coding regions, focusing on sequencing exomes rather than whole genomes is efficient in terms of time, expense and coverage 5 . Recent studies have successfully used WES technology to identify variants that strongly correlate with disease phenotypes 19, 20, 46, 47 . However, high-resolution examination of different WES datasets shows uneven coverage along the length of exons, which could cause possible problems in variant calling analysis.…”

Section: Discussionmentioning

confidence: 99%

Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity

Wang

Shashikant

Jensen

et al. 2017

Sci Rep

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Whole Exome Sequencing (WES) is a powerful clinical diagnostic tool for discovering the genetic basis of many diseases. A major shortcoming of WES is uneven coverage of sequence reads over the exome targets contributing to many low coverage regions, which hinders accurate variant calling. In this study, we devised two novel metrics, Cohort Coverage Sparseness (CCS) and Unevenness (U E ) Scores for a detailed assessment of the distribution of coverage of sequence reads. Employing these metrics we revealed non-uniformity of coverage and low coverage regions in the WES data generated by three different platforms. This non-uniformity of coverage is both local (coverage of a given exon across different platforms) and global (coverage of all exons across the genome in the given platform). The low coverage regions encompassing functionally important genes were often associated with high GC content, repeat elements and segmental duplications. While a majority of the problems associated with WES are due to the limitations of the capture methods, further refinements in WES technologies have the potential to enhance its clinical applications.

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“…Biesecker and Green have reported that “pretest counseling is particularly important, to maintain realistic expectations for finding the causative variant and to alert the patient or family that in most cases, a positive result is unlikely to change treatment or management decisions or to improve the prognosis.” 5 Parents should be helped to understand that the most common consequence of a molecular diagnosis in a sick newborn is the confirmation of an unalterable, bleak prognosis, a result that is not the “clinically actionable results” “or “clinical utility” that parents and healthcare professionals might hope for 43 but that be actionable in a broader sense because it can allow parents to make decisions about medical care.…”

Section: Sequencing To Diagnose Sick Newborns Can Benefit Children Anmentioning

confidence: 99%

Sequencing Newborns:A Call for Nuanced Use of Genomic Technologies

Johnston¹,

Lantos²,

Goldenberg³

et al. 2018

Hastings Center Report

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Many scientists and doctors hope that affordable genome sequencing will lead to more personalized medical care and improve public health in ways that will benefit children, families, and society more broadly. One hope in particular is that all newborns could be sequenced at birth, thereby setting the stage for a lifetime of medical care and self-directed preventive actions tailored to each child's genome. Indeed, commentators often suggest that universal genome sequencing is inevitable. Such optimism can come with the presumption that discussing the potential limits, cost, and downsides of widespread application of genomic technologies is pointless, excessively pessimistic, or overly cautious. We disagree. Given the pragmatic challenges associated with determining what sequencing data mean for the health of individuals, the economic costs associated with interpreting and acting on such data, and the psychosocial costs of predicting one's own or one's child's future life plans based on uncertain testing results, we think this hope and optimism deserve to be tempered. In the analysis that follows, we distinguish between two reasons for using sequencing: to diagnose individual infants who have been identified as sick and to screen populations of infants who appear to be healthy. We also distinguish among three contexts in which sequencing for either diagnosis or screening could be deployed: in clinical medicine, in public health programs, and as a direct-to-consumer service. Each of these contexts comes with different professional norms, policy considerations, and public expectations. Finally, we distinguish between two main types of genome sequencing: targeted sequencing, where only specific genes are sequenced or analyzed, and whole-exome or whole-genome sequencing, where all the DNA or all the coding segments of all genes are sequenced and analyzed. In a symptomatic newborn, targeted or genome-wide sequencing can help guide other tests for diagnosis or for specific treatment that is urgently needed. Clinicians use the infant's symptoms (or phenotype) to interrogate the sequencing data. These same complexities and uncertainties, however, limit the usefulness of genome-wide sequencing as a population screening tool. While we recognize considerable benefit in using targeted sequencing to screen for or detect specific conditions that meet the criteria for inclusion in newborn screening panels, use of genome-wide sequencing as a sole screening tool for newborns is at best premature. We conclude that sequencing technology can be beneficially used in newborns when that use is nuanced and attentive to context.

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Genome-Scale Sequencing in Clinical Care

Cited by 22 publications

References 10 publications

Genetics of Disorders of Sex Development

Genetics of Disorders of Sex Development

Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity

Sequencing Newborns:A Call for Nuanced Use of Genomic Technologies

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