Next-Generation Sequencing to Diagnose Suspected Genetic Disorders

Adams, David R.; Eng, Christine M.

doi:10.1056/nejmra1711801

Cited by 203 publications

(180 citation statements)

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“…Finally, in some instances the clinical value of genetic testing may only emerge over time through clinical research initiatives. For example, the collection and sharing of detailed phenotypic and genetic data from patients with ultrarare disorders may facilitate novel disease‐gene discovery . Any potential clinical benefits of testing must be counterbalanced against any harm that might arise, which could include negative psychological impacts of being labelled with a genetic diagnosis; guilt over transmission to family members; and the potential for stigmatization and/or negative discrimination.…”

Section: Application Of Genetic Testingmentioning

confidence: 99%

“…High‐resolution DNA sequencing is required for the diagnosis of the majority of monogenic disorders, although the content of available tests varies by several orders of magnitude (Figure ) . Whilst the sequencing of individual genes by Sanger‐based methods has been the mainstay of genetic testing over the past decades, NGS‐based methods are increasingly employed, providing a highly cost‐effective and time‐efficient method for genetic diagnosis . Determining the optimal strategy for DNA sequencing is dependent on the clinical setting and in particular the degree of genetic heterogeneity associated with the specific phenotype or disorder (Figure ).…”

Section: Germline Genetic Testing – Selecting the Optimal Testmentioning

confidence: 99%

“…The fundamental advance of any of the NGS methods is the concept of “massive parallel sequencing,” which describes the simultaneous automated acquisition of DNA sequence of millions of short DNA fragments, which are subsequently assembled into meaningful data by aligning to a reference genome . The genomic content of the test is determined by the degree of enrichment of specific DNA regions prior to sequencing.…”

Section: Germline Genetic Testing – Selecting the Optimal Testmentioning

confidence: 99%

“…These advances now offer many new opportunities for genetic testing in the clinical setting and the potential for improved health outcomes. At the same time, the increased use of genetic testing brings many challenges, not least those associated with accurate test interpretation and deciphering the impact of genetic variation on human health . Therefore, prior to the widespread adoption of new testing strategies it is important to consider both the potential utility and the validity of any given test, as well as evaluating any harm that may arise.…”

Section: Introductionmentioning

confidence: 99%

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Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

Newey

2019

Clinical Endocrinology

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Recent advances in DNA sequencing technology have led to an unprecedented period of disease‐gene discovery offering many new opportunities for genetic testing in the clinical setting. Endocrinology has seen a rapid expansion in the taxonomy of monogenic disorders, which can be detected by an expanding portfolio of genetic tests in both diagnostic and predictive settings. Successful testing relies on many factors including the ability to identify those at increased risk of genetic disease in the busy clinic as well as a working knowledge of the various testing platforms and their limitations. The clinical utility of a given test is dependent upon many factors, which include the reliability of the genetic testing platform, the accuracy of the test result interpretation and knowledge of disease penetrance and expression. The increasing adoption of “high‐content” genetic testing based on next‐generation sequencing (NGS) to diagnose hereditary endocrine disorders brings a number of challenges including the potential for uncertain test results and/or genetic findings unrelated to the indication for testing. Therefore, it is increasingly important that the clinician is aware of the current evolution in genetic testing, and understands the different settings in which it may be employed. This review provides an overview of the genetic testing workflow, focusing on each of the major components required for successful testing in adult and paediatric endocrine settings. In addition, the challenges of variant interpretation are highlighted, as are issues related to informed consent, prenatal diagnosis and predictive testing. Finally, the future directions of genetic testing relevant to endocrinology are discussed.

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Section: Application Of Genetic Testingmentioning

confidence: 99%

Section: Germline Genetic Testing – Selecting the Optimal Testmentioning

confidence: 99%

Section: Germline Genetic Testing – Selecting the Optimal Testmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

Newey

2019

Clinical Endocrinology

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“…Mass screening studies using determination of ceruloplasmin in urine 8 or blood 9 indicated a substantially higher prevalence (1-2 in 3000). 12 If two mutations are detected in an asymptomatic individual, the question will arise whether the genetic finding can be translated to the presence of a disease. 10 Furthermore, another study 11 in France showed a high heterozygous carrier frequency of ATP7B yielding a prevalence of 1:31 subjects.…”

Section: Introductionmentioning

confidence: 99%

The dilemma to diagnose Wilson disease by genetic testing alone

Stättermayer

Entenmann

Gschwantler

et al. 2019

Eur J Clin Investigation

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Background Wilson disease (WD) is an autosomal recessive disorder of hepatic copper excretion. About sixty per cent of patients present with liver disease. WD is considered a fatal disease if undiagnosed and/or untreated but recent data indicate that disease penetrance may not be 100%. Materials and Methods All patients underwent liver biopsy as part of the diagnostic workup. Genetic testing for ATP7B was performed by Sanger sequencing. Results We report on a large family with multiple affected siblings. The first patient (male, 31 years) underwent orthotopic liver transplantation (OLT) because of fulminant WD. He was homozygous for p.G710A. One asymptomatic brother (37 years) had the same mutation. He is doing well on chelation therapy. Fifteen years later, a second‐degree sibling (female, 16 years) presented with fulminant WD and underwent OLT. She was compound heterozygote (p.G710A/p.G710S). Further family screening revealed a third mutation (p.V536A) in a female (21 years) and male (16 years) compound‐heterozygote sibling (p.G710A/p.V536A). In both, serum ceruloplasmin and 24‐hour urinary copper excretion were normal. Liver biopsy showed normal histology and a quantitative hepatic copper content within the normal range or only slightly elevated (19 and 75 μg/g dry weight, respectively). No decoppering treatment was initiated so far. Conclusion Genetic testing alone is not always sufficient to diagnose WD in asymptomatic patients, and human mutation databases should be used with caution. Even patients carrying two disease‐causing mutations do not necessarily have demonstrable alteration of copper metabolism. Asymptomatic siblings diagnosed by genetic screening require further testing before initiating treatment.

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The Path to Genomic Screening—Far From Simple, but the Journey Has Begun

Berg

2024

JAMA

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Next-Generation Sequencing to Diagnose Suspected Genetic Disorders

Cited by 203 publications

References 49 publications

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

The dilemma to diagnose Wilson disease by genetic testing alone

The Path to Genomic Screening—Far From Simple, but the Journey Has Begun

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