Clinical Genomics - 1st Edition - ISBN: 9780124047488, 9780124051737

Clinical Genomics

1st Edition

Editors: Shashikant Kulkarni John Pfeifer
eBook ISBN: 9780124051737
Hardcover ISBN: 9780124047488
Imprint: Academic Press
Published Date: 1st October 2014
Page Count: 488
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Clinical Genomics provides an overview of the various next-generation sequencing (NGS) technologies that are currently used in clinical diagnostic laboratories. It presents key bioinformatic challenges and the solutions that must be addressed by clinical genomicists and genomic pathologists, such as specific pipelines for identification of the full range of variants that are clinically important.

This book is also focused on the challenges of diagnostic interpretation of NGS results in a clinical setting. Its final sections are devoted to the emerging regulatory issues that will govern clinical use of NGS, and reimbursement paradigms that will affect the way in which laboratory professionals get paid for the testing.

Key Features

  • Simplifies complexities of NGS technologies for rapid education of clinical genomicists and genomic pathologists towards genomic medicine paradigm
  • Tried and tested practice-based analysis for precision diagnosis and treatment plans
  • Specific pipelines and meta-analysis for full range of clinically important variants


Clinical Genomicists, Molecular Pathologists, molecular Geneticists, clinical Cytogeneticists, Clinical Geneticists, Primary Care Physicians (including Oncologists, Pediatricians, Neurologists, Cardiologists, and Neonatologists) and Genetic Counselors seeking to use or interpret Next Gen Sequencing in the diagnosis, prognosis, and management of inherited and somatic disorders in the era of precision medicine.

Table of Contents

  • Dedication
  • List of Contributors
  • Foreword
    • Reference
  • Preface
  • Acknowledgments
  • Section I: Methods
    • Chapter 1. Overview of Technical Aspects and Chemistries of Next-Generation Sequencing
      • Clinical Molecular Testing: Finer and Finer Resolution
      • Sanger Sequencing
      • Cyclic Array Sequencing
      • Illumina Sequencing
      • SOLiD Sequencing
      • Ion Torrent Sequencing
      • Roche 454 Genome Sequencers
      • Third-Generation Sequencing Platforms
      • References
    • Chapter 2. Clinical Genome Sequencing
      • Key Concepts
      • Introduction
      • Applications and Test Information
      • Laboratory Process, Data Generation, and Quality Control
      • Conclusion
      • References
    • Chapter 3. Targeted Hybrid Capture Methods
      • Key Concepts
      • Introduction
      • Basic Principles of Hybrid Capture-Based NGS
      • Hybrid Capture-Based Target Enrichment Strategies
      • Clinical Applications of Target Capture Enrichment
      • Variant Detection
      • Practical and Operational Considerations
      • Conclusions
      • References
    • Chapter 4. Amplification-Based Methods
      • Introduction
      • Principles of Amplification-Based Targeted NGS
      • Nucleic Acids Preparation
      • Primer Design for Multiplex PCR
      • Library Preparation and Amplification
      • Other Amplification-Based Target Enrichment Approaches
      • Comparison of Amplification- and Capture-Based Methods
      • Clinical Applications
      • Conclusion
      • References
    • Chapter 5. Emerging DNA Sequencing Technologies
      • Key Concepts
      • Introduction
      • Third-Generation Sequencing Approaches
      • Fourth-Generation Sequencing
      • Selected Novel Technologies
      • Summary
      • References
    • Chapter 6. RNA-Sequencing and Methylome Analysis
      • Key Concepts
      • Introduction
      • Approaches to Analysis of RNA
      • Workflow
      • Utility of RNA-Seq to Characterize Alternative Splicing Events
      • Utility of RNA-Seq for Genomic Structural Variant Detection
      • RNA-Seq: Challenges, Pitfalls, and Opportunities in Clinical Applications
      • Methylome Sequencing
      • Conclusions
      • References
  • Section II: Bioinformatics
    • Chapter 7. Base Calling, Read Mapping, and Coverage Analysis
      • Key Concepts
      • Introduction
      • Platform-Specific Base Calling Methods
      • Read Mapping
      • Coverage Analysis: Metrics for Assessing Genotype Quality
      • Summary
      • References
    • Chapter 8. Single Nucleotide Variant Detection Using Next Generation Sequencing
      • Key Concepts
      • Introduction
      • Sources of SNVs
      • Consequences of SNVs
      • Technical Issues
      • Bioinformatic Approaches for SNV Calling
      • Interpretation of SNVs
      • Reporting
      • Summary
      • References
    • Chapter 9. Insertions and Deletions (Indels)
      • Key Concepts
      • Overview of Insertion/Deletion Events (Indels)
      • Sources, Frequency, and Consequences of Indels
      • Technical Issues That Impact Indel Detection by NGS
      • Specimen Issues That Impact Indel Detection by NGS
      • Bioinformatics Approaches to NGS Indel Detection
      • Summary
      • References
    • Chapter 10. Translocation Detection Using Next-Generation Sequencing
      • Key Concepts
      • Introduction to Translocations
      • Translocations in Human Disease
      • Translocation Detection
      • Informatic Approaches to Translocation Detection
      • Translocation Detection in Clinical Practice
      • Summary and Conclusion
      • References
    • Chapter 11. Copy Number Variant Detection Using Next-Generation Sequencing
      • Key Concepts
      • Overview of Copy Number Variation and Detection via Clinical Next-Generation Sequencing
      • Sources, Frequency, and Functional Consequences of Copy Number Variation in Humans
      • CNV Detection in Clinical NGS Applications
      • Conceptual Approaches to NGS CNV Detection
      • Detection in the Clinic: Linking Application, Technical Approach, and Detection Methods
      • Reference Standards
      • Orthogonal CNV Validation
      • Summary and Conclusion
      • References
  • Section III: Interpretation
    • Chapter 12. Reference Databases for Disease Associations
      • Key Concepts
      • Introduction
      • Identification and Validation of Human Variation
      • Identification of Common Variation
      • Interpretation of Common Variation
      • Defining Diseases and Phenotypes
      • Representation of Variation Data in Public Databases
      • Data Access and Interpretation
      • Determination of Variant Pathogenicity
      • Global Data Sharing
      • Conclusion
      • References
    • Chapter 13. Reporting of Clinical Genomics Test Results
      • Key Concepts
      • Introduction
      • Components of the Written NGS Report
      • Beyond the Written Report: Other NGS Reporting Issues to Consider
      • Conclusion
      • References
    • Chapter 14. Reporting Software
      • Key Concepts
      • Introduction
      • Clinical Genomic Test Order Entry
      • Laboratory Information Management Systems (LIMS) Tracking
      • Analytics: From Reads to Variant Calls
      • Analytics: Variant Annotation and Classification
      • Variant Interpretation
      • Final Report Transmission to the EMR
      • Leveraging Standards in Clinical Genomics Software Systems
      • Regulatory Compliance
      • Support Personnel
      • Conclusion
      • References
    • Chapter 15. Constitutional Diseases: Amplification-Based Next-Generation Sequencing
      • Key Concepts
      • Introduction
      • Multigene Panel Validation
      • Clinical Workflow
      • Conclusion
      • References
    • Chapter 16. Targeted Hybrid Capture for Inherited Disease Panels
      • Introduction
      • Target Selection Using Hybridization-Based Capture
      • Design and Implementation of Targeted Hybridization-Based Capture Panels
      • Targeted Hybrid Capture: Selecting a Panel for Constitutional Diseases
      • Applications in Clinical Practice: Lessons Learned
      • References
    • Chapter 17. Constitutional Disorders: Whole Exome and Whole Genome Sequencing
      • Key Concepts
      • Introduction
      • Genomic Sequencing
      • Analyzing Individual and Multiple Data Sets for Causal Mutation Discovery
      • Conclusion and Future Directions
      • Acknowledgment
      • References
    • Chapter 18. Somatic Diseases (Cancer): Amplification-Based Next-Generation Sequencing
      • Introduction
      • NGS Technologies
      • Amplification-Based NGS Technologies
      • Advantages and Disadvantages of Amplification-Based NGS
      • Clinical Application of Amplification-Based NGS in Cancer
      • Data Analysis
      • Interpretation and Reporting
      • Challenges and Perspectives
      • References
    • Chapter 19. Targeted Hybrid-Capture for Somatic Mutation Detection in the Clinic
      • Key Concepts
      • Introduction
      • Clinical Utility of Somatic Mutation Detection in Cancer
      • Description of Hybridization-Based Methodology
      • Utility of Targeted Hybrid Capture
      • NGS in a Clinical Laboratory Setting
      • Conclusion
      • References
    • Chapter 20. Somatic Diseases (Cancer): Whole Exome and Whole Genome Sequencing
      • Key Concepts
      • Introduction to Exome and Genome Sequencing in Cancer
      • Interpretative Considerations in Exome and Genome Cancer Sequencing
      • Analytic Considerations for Exome and Genome Sequencing in Cancer
      • Summary
      • References
  • Section IV: Regulation, Reimbursement, and Legal Issues
    • Chapter 21. Assay Validation
      • Key Concepts
      • Introduction
      • NGS Workflow
      • The Regulatory and Professional Framework for Assuring Quality
      • Assay Validation
      • Accuracy
      • Precision
      • Analytical Sensitivity and Analytical Specificity
      • Reportable and Reference Ranges
      • Quality Control
      • Reference Materials
      • Conclusion
      • Acknowledgment
      • References
    • Chapter 22. Regulatory Considerations Related to Clinical Next Generation Sequencing
      • Key Points
      • Introduction
      • Regulatory Standards
      • FDA Oversight of Clinical NGS
      • Total Quality Management: QC
      • Total Quality Management: QA
      • Conclusion
      • References
    • Chapter 23. Genomic Reference Materials for Clinical Applications
      • Introduction
      • Genome in a Bottle Consortium
      • Reference Data
      • Other Reference Materials for Genome-Scale Measurements
      • Conclusion
      • References
    • Chapter 24. Ethical Challenges to Next-Generation Sequencing
      • Key Concepts
      • Introduction
      • Challenging Existing Frameworks
      • Notifying of Results
      • Privacy and Confidentiality
      • Informed Consent
      • Conclusion
      • References
    • Chapter 25. Legal Issues
      • Introduction
      • Patent Overview
      • History of Gene Patents
      • Arguments for and Against Gene Patents
      • Important Legal Cases
      • Implication of Recent Court Decisions for Genetic Testing
      • Genetic Information Nondiscrimination Act
      • References
    • Chapter 26. Billing and Reimbursement
      • Key Concepts
      • Introduction
      • Insurance Payers
      • Reimbursement Processes
      • Test Design Factors That Impact Reimbursement
      • Patient Protection and Affordable Care Act
      • Cost Structure
      • Summary
      • References
  • Index


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© Academic Press 2015
Academic Press
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About the Editor

Shashikant Kulkarni

Dr. Shashikant Kulkarni is the Head of Clinical Genomics, Genomics and Pathology Services and also the Director of Cytogenomics and Molecular Pathology at Washington University School of Medicine. In addition, he is Associate Professor of Pathology and Immunology, Pediatrics, and Genetics. His lab's principle research interest is delineation of novel genomic structural and single nucleotide variants in cancer.

Affiliations and Expertise

Head of Clinical Genomics, Genomics and Pathology Services, and Director of Cytogenomics and Molecular Pathology at Washington University School of Medicine

John Pfeifer

Affiliations and Expertise

Vice Chair for Clinical Affairs, Pathology and Immunology; Professor of Pathology and Immunology, Obstetrics and Gynecology at Washington University School of Medicine


"...presents key bioinformatic challenges and the solutions that must be addressed by clinical genomicists and genomic pathologists, such as specific pipelines for identification of the full range of variants that are clinically important." --Anticancer Research, February 2015