Transcript Clinical genomics - University of Toledo

Establishing a Clinical Genomics
Program at an Academic Medical Center
Jason Merker, M.D., Ph.D.
Co-director, Stanford Clinical Genomics Service
Regional APC/PDAS Meeting, Kauai
10/23/2014
Introduction to Clinical Genomics
(in 5 Slides)
Wellcome Collection – Medicine Now
3.4 billion units of DNA code:
• 127 volumes
• 1,000 pages per volume
Size of targeted regions in assays
Genome – 127 volumes
Exome – 2.5 volumes
500 gene panel – 40 pages
50 gene panel – 4 pages
Single gene – <1/10 of a page
Tumor/Normal or
Trio Genome
Sequencing Data
Limit of detection - % allele burden
Assay type
Genome sequencing
Exome sequencing
NGS-based gene panels
Sanger sequencing
Single mutation assay
Average limit of detection
(% allele burden)
~20 – 30%
~20 – 30%
5 – 10%
20%
<10%
Some mutation types are difficult to detect by
genome or exome sequencing technologies
Mutation type
Single nucleotide variant
Small indels (<10-20 bp)
Copy-number variants
Structural variants
Larger indels
Difficulty
Introduction to Clinical Genomics
at Stanford
Clinical Genomics Efforts at Stanford
Basic, Translational,
and Clinical Research
Clinical Genomics
Service
GenePool Biobank
Advisory Committee for Clinical Genomics
Name
Organization/Department
Director’s Role
C. Dawes
Stanford Children’s Health
CEO
L. Minor
School of Medicine
Dean
A. Rubin
Stanford Health Care
President and CEO
T. Quertermous*
CV Med
GenePool Biobank
J. Ford*
Oncology
Cancer Institute Genomics Programs
Chief Cancer Genetics
E. Ashley
CV Med
Co-director Clinical Genomics Service
Institute for Inherited CV Disease
L. Boxer
Hematology
Vice Dean
A. Butte
Pediatrics
Chief Division of Systems Medicine
M. Cho
Pediatrics
Center for Biomedical Ethics
L. Hudgins
Pediatrics
Chief Medical Genetics
J. Merker
Pathology
Co-director Clinical Genomics Service
K. Ormond
Genetics
Genetics and Genomics Counseling Program
I. Schrijver
Pathology
Molecular Pathology Laboratory
M. Snyder
Genetics
Chair Genetics
Director Center for Genomics & PM
Stanford Clinical Genomics Service
• Directors – Jason Merker (Path), Euan Ashley (CV Med)
• Department – Pathology
• Goal – Build a clinical laboratory service at Stanford
University Medical Center that uses genome
sequencing to evaluate adult and pediatric patients
with unexplained genetic diseases.
• Pilot – Develop analysis/curation pipeline and perform
genome sequencing on 4 patient populations (100
cases total):
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Heritable cancer predisposition
Heritable cardiovascular disorders
Pediatric syndromes
Familial adverse drug reactions or sensitivity
Workflow – 1
Genetic
Counselor
Treating
Team
Biocurator
MP/MG
Test Request
Patient and
physician
request genome
sequencing
for heritable
disease through
EMR
Review by Genetic
Test Consultation Service
• Genetic Counselor
• Molecular Pathologist
• Medical Geneticist
Analysis
Team
Outside
Faculty
Expert (prn)
Establish questions being posed by
patient and treating team
• Genetic?
• Candidate variants and analysis
approach
• Clinical use
Workflow – 2
Insurance
authorization
Patient meets with genetic
counselor
• Clinical counseling & consent
• *Options for return of
secondary findings
• 2-step consent process for
non-actionable findings
• Biobanking and data-sharing
counseling & consent
Blood draw
• 1 tube for genome
sequencing
• 1 tube for confirmatory
studies and specimen ID
• 1 tube for biobanking
(with appropriate consent)
Workflow – 3
Illumina genome
sequencing
Data analysis (open source,
commercial, and Stanford
developed):
• Alignment
• Variant calling
• Quality management
• ID and gender checks to
confirm specimen identity
Variant filtering/prioritization
• Phenotype
• Inheritance pattern
• Predicted deleterious
• Secondary findings
Workflow – 4
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Variant verification by
orthogonal method
• Segregation analysis
Curation
meeting and
draft report
Genomics Review Boards
Genomics Review Groups
• Genomics Service
• Treating Team
• Content expert
Pediatrics
Cardiovascular
Oncology
Pharmacogenomics
Workflow – 5
Final report
generated and
uploaded to EMR
Patient meets with genetic
counselor and relevant
members of treatment team
Yearly re-analysis upon
request
• Improved analysis
• Improved sequencing
• Increased medical
knowledge
Case 1 – 30 YOM w/ DCM
• TTN A-band truncating variant that segregates
with disease in large family – likely pathogenic
• RYR1 variant (malignant hyperthermia) – likely
pathogenic vs. variant of uncertain significance
Case 2
Clinical Genetic Test Consultation
Service
Clinical Genetic Test Consultation Service
Rationale #1 – The number of clinical genetic tests is
becoming unmanageable
The CDC estimates that genetic tests for use in the clinical setting have been
developed for approximately 2,000 diseases
Clinical Genetic Test Consultation Service
Rationale #2 – The number of misorders for complex
genetic testing is high
“Approximately 25% of all requests for complex
genetic tests assessing germ line mutations were
changed following review.”
Miller CE et al. 2014. Am J Med Genet Part A 164A:1094–1101.
Clinical Genetic Test Consultation Service
– Summary of rationales
• The number, indications, and complexity of genetic
tests offered have been increasing, and will continue to
do so for the foreseeable future.
• It is therefore not surprising that mistakes often occur
in the ordering of complex genetic tests.
• Incorrect ordering of genetic tests results in
unnecessary costs to the healthcare system, but more
importantly adversely affects the care of our patients
– Failure or delays in getting the needed test results
– Communication of results from the incorrect test
– Providing genetic information that was neither requested
nor desired by the patient
Clinical Genetic Test Consultation Service
– Personnel
Molecular
Pathologist
Genetic
Counselor
Medical
Geneticist
Clinical Genetic Test Consultation Service
1. Provide consultation to SUMC healthcare providers
needing further information on available genetic testing.
2. Review all quests for send-out genetic testing from
Stanford Clinical Laboratories to identify and help correct
genetic test misorders.
3. Work with Genetic Test Utilization Committee develop
innovative, provider-friendly ways to educate our
physicians about genetic test utilization (e.g., pop-up
windows in EMR offering test consultation or other
educational information).
4. Assist departments and divisions with educational
activities related to genetic test utilization (e.g., seminars,
presentation to new residents) and with establishing
protocols for genetic test ordering for common use cases
Clinical genomics educational efforts
Open Didactic Core Curriculum in
Genomic Medicine
1. Experimental methods for measuring and manipulating
DNA/RNA
2. Fundamentals of human genetic variation
3. Microarrays and analysis of hybridization data
4. Sequencing methods
5. Heritable genetic disorders
6. Acquired mutations in human cancers I: solid tumors
7. Acquired mutations in human cancers II: hematopoietic
malignancies
8. Pharmacogenomics
9. HLA genetics
10. Ethical, legal, and economic implications of clinical
genomic testing
Schrijver I et al. J Mol Diagn. 2013;15:141.
Elective Course in Advanced
Genomic Medicine
1. Next-generation sequencing methods 2.0
2. Human genetic variation 2.0
3. DNA sequence analysis methods I: sequence
databases and files
4. DNA sequence analysis methods II: sequence
alignment algorithms
5. DNA sequence analysis methods III: genome assembly
and analysis
6. Introduction to scripting programming languages
7. Statistical tools for sequence analysis and genomics
Schrijver I et al. J Mol Diagn. 2013;15:141.
Elective Course in Advanced
Genomic Medicine
1. Next-generation sequencing methods 2.0
2. Human genetic variation 2.0
3. DNA sequence analysis methods I: sequence
databases and files
4. DNA sequence analysis methods II: sequence
alignment algorithms
5. DNA sequence analysis methods III: genome assembly
and analysis
6. Introduction to scripting programming languages
7. Statistical tools for sequence analysis and genomics
Schrijver I et al. J Mol Diagn. 2013;15:141.
New Elective Course in Advanced
Genomic Medicine
• Genome and exome
analysis for heritable
disease
• Tumor/normal
sequencing analysis
• RNA sequencing
analysis
• Unix commands and
basic scripting
End