Author: Kevin Davies, PhD
This report explores the recent surge in clinical genome sequencing, from the
point of view of the sequencing providers, the medical organizations
delivering these services, and the start-ups offering a variety of
interpretation services, platforms, and business models. Aspects discussed and
- Progress in clinical genome sequencing
- Organizations leading the way in generating clinical data and its
- Determining the causality of documented variants in genetic disease.
- Clinical genome sequencing in oncology.
- Academic and commercial clinical genomics providers.
- The next-gen sequencing landscape.
- Companies providing genome interpretation software.
- Initiatives in setting sequencing standards.
- Interviews with six industry experts, conducted exclusively for this
- Results of a custom survey on clinical genome sequencing.
- A list of print and online resources for further investigation into this
For many years now, next-generation sequencing (NGS) has been used in clinical
research, building on the success of being able to sequence personal genomes
affordably, and turning that technology into defining the mutation profile of
rare Mendelian diseases and cancer. With the first report of successful exome
sequencing in a patient with a mystery illness, the clinical community has
embraced NGS-performed in CLIA- and CAP-certified laboratories-for diagnostic
Nevertheless, at the $1,000-5,000 price point, medical practitioners face a
dilemma: It is possible to offer to sequence the exome or complete genome of a
patient for roughly the same price as a traditional patented genetic
diagnostic test or gene panel. Economics alone would appear to dictate that
the practice of medical genetics and clinical diagnostics must evolve
radically in the face of the remarkable advances in NGS. That sentiment has
been bolstered in recent years with more and more anecdotal stories of the
identification of mutations in patients suffering mysterious/undiagnosed
(presumably) genetic disorders. Emboldened by these success stories, medical
centers, sequencing platform providers, and diagnostics companies are
rethinking their strategies for delivering exome and/or whole-genome
In a further irony, the cost of sequencing has fallen so fast that it is now a
relatively trivial component of the full array of services required to deliver
clinical genome information-what some have (literally or tongue-in-cheek)
called the $100,000 or $1 million interpretation. Leaving aside the
apples-and-oranges debate of the precise cost of genome interpretation, there
is no doubt that 2012 proved to be a stunning year for the maturation of
clinical genome testing. Several prominent, public stories relating to the
successful end of diagnostic odysseys provide gratifying examples of the
potential of this technology. Cases of families receiving a confirmed
diagnosis after years of false hope and hundreds of thousands of dollars in
medical costs show the benefit of this approach, and beg the question of how
long the molecular diagnostics industry will continue in its
single-gene/multigene panel approach. (After all, the exome is essentially
just one giant gene panel with 22,000 genes.)
Exciting, remarkable progress in clinical genome sequencing is being fueled by
steady advances in existing platforms, the arrival of new diagnostic
platforms, and improvements in genome analysis software. That said, the
adoption of clinical NGS is not trivial, and many questions still remain about
setting standards, ensuring analytic and clinical validity of the tests, and
About the Author
Kevin Davies, PhD, is the founding editor of Bio-IT World and the journal
Nature Genetics. He is the author of three books that explore the impact of
technology and genomics in medicine, most recently "The $1,000 Genome" (Free
Press, 2010). Kevin also serves as an advisor to Cambridge Healthtech
Associates and blogs at NGS Leaders.
Table of Contents
Chapter 1 - PROGRESS IN CLINICAL GENOME SEQUENCING
- 1.1. Proof of Concept
- 1.2. From Known to Unknown
- 1.3. Ending Diagnostic Odysseys
- 1.4. Search Strategy
- 1.5. Causal Variants and Databases
- 1.6. Cancer Genomics
- 1.7. Conclusions
Chapter 2 - CLINICAL GENOMICS PIONEERS AND PROVIDERS
- 2.1. Academic Medical Centers
- Medical College of Wisconsin
- Baylor Whole Genome Laboratory
- UCLA Medical Genetics Clinic
- Children's Hospital of Philadelphia (CHOP)
- Emory Genetics Laboratory
- Genomics and Pathology Services, Washington University in St. Louis
- Fox Chase Cancer Center, Philadelphia
- 2.2. Commercial Sector
- Ambry Genetics
- Foundation Medicine
- Courtagen Life Sciences
- GeneInsight-Illumina Network
Chapter 3 - CLINICAL-GRADE SEQUENCING
- 3.1. The Next-Gen Sequencing Landscape
- Illumina HiSeq/MiSeq
- Ion Torrent
- Complete Genomics
- Pacific Biosciences (PacBio)
- Nanopore Sequencing: Oxford Nanopore, Genia Technologies, and More
- Oxford Nanopore
- Genia Technologies
- Other Technologies
- 3.2. Genome Interpretation Software
- Ingenuity Systems
- SV Bio
- Cypher Genomics
- InVitae Corporation
- Station X
- 3.3. Genome Standards
- The CLARITY Challenge
- Sequencing Standards
- Genome in a Bottle
- The Archon Genomics X PRIZE
Chapter 4 - INSIGHT PHARMA REPORTS' CLINICAL GENOMICS SURVEY
- Survey Questions:What Type of Lab Do You Work In?
- Is Your Facility CLIA-Certified?
- Is Your Facility CAP-Certified?
- Where Is Your Facility Located?
- Which Sequencing Instruments Do You Use and How Many of Each Do You Have?
- Have You Outsourced To Any Sequencing Provider?
- Which Sequencing Providers Have You Used?
- What Is the Primary Sequencing Work Done In Your Lab?
- Are You Considering Purchasing Any New Sequencing Equipment In the Next 12
- Which Sequencing Platforms Are You Considering Purchasing and How Many?
- What Type of Commercial Mapping/Assembly/Variant Caller Platform Do You
- What Other NGS Software/Platforms Do You Principally Use?
- What Software Do You Use for Medical Genome Interpretation?
- What Would You Estimate the Cost of Delivering a Medical-Grade Genome to
- What Do You Consider the Biggest Challenge In Integrating Whole-Genome
Sequencing Into The Clinic?
- Do You Have Any Experience Storing or Analyzing NGS Data In the Cloud?
- Would You Put Clinical Data In the Cloud?
Chapter 5 - THOUGHT LEADER INTERVIEWS
- 5.1. Nazneen Aziz, PhD
- Director of Molecular Medicine, Transformation Program Office, College
of American Pathologists (CAP)
- 5.2. Elizabeth Worthey, PhD
- Assistant Professor, Medical College of Wisconsin
- 5.3. Ashley Van Zeeland, PhD
- CEO, Cypher Genomics, San Diego, CA
- 5.4. Ron Ranauro
- Founder/Managing Partner, Incite Advisors
- 5.5. Karen Seibert, PhD
- Professor, Department of Genetics, Washington University in St. Louis
- Director, Genetics and Pathology Services (GPS@WUSTL), Washington
University School of Medicine
- 5.6. Catherine Brownstein, MPH, PhD
- Project Manager, The Gene Partnership's Research Sequencing Division,
Boston Children's Hospital
- Figure 1.1. Filtration Decision Tree for Genomic Variants
- Figure 2.1. GeneDx Letter for Pre-Authorization (Edited)
- Figure 3.1. The Rapidly Falling Cost of Genome Sequencing
- Figure 4.1. What Type of Lab Do You Work In?
- Figure 4.2. Is Your Facility CLIA-Certified?
- Figure 4.3. Is Your Facility CAP-Certified?
- Figure 4.4. Where Is Your Facility Located?
- Figure 4.5. Which Sequencing Instruments Do You Use and How Many of Each
Do You Have?
- Figure 4.6. Have You Outsourced To Any Sequencing Provider?
- Figure 4.7. Which Sequencing Providers Have You Used?
- Figure 4.8. What Is the Primary Sequencing Work Done In Your Lab?
- Figure 4.9. Are You Considering Purchasing Any New Sequencing Equipment In
the Next 12 Months?
- Figure 4.10. Which Sequencing Platforms Are You Considering Purchasing and
- Figure 4.11. What Type of Commercial Mapping/Assembly/Variant Caller
Platform Do You Mostly Use?
- Figure 4.12. What Other NGS Software/Platforms Do You Principally Use?
- Figure 4.13. What Software Do You Use for Medical Genome Interpretation?
- Figure 4.14. What Would You Estimate the Cost of Delivering a
Medical-Grade Genome to Be?
- Figure 4.15. What Do You Consider the Biggest Challenge In Integrating
Whole-Genome Sequencing Into The Clinic?
- Figure 4.16. Do You Have Any Experience Storing or Analyzing NGS Data In
- Figure 4.17. Would You Put Clinical Data In the Cloud?
- Table 1.1. Proof-of-Concept Identification of Mutation in Freeman-Sheldon
- Table 1.2. Companies Applying NGS Toward Cancer Diagnostics and Treatment
- Table 3.1. Projected Sequence Throughput for Ion Proton Chips
- Table 3.2. Potential Advantages of Nanopore Sequencing
- Table 3.3. Comparison of HugeSeq to Other Genome Analysis Platforms
- Table 3.4. Categorization of Clinical Variants by InVitae
- Table 3.5. The CLARITY Challenge Contestants and Finalists