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)

3.4 billion units of DNA code:
• 127 volumes
• 1,000 pages per volume

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

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 Difficulty
Single nucleotide variant
Small indels (<10-20 bp)
Copy-number variants
Structural variants
Larger indels

Introduction to Clinical Genomics at Stanford

Basic, Translational, and Clinical Research
Clinical Genomics
Service
GenePool Biobank

Advisory Committee for Clinical Genomics
Name
C. Dawes
Organization/Department Director’s Role
Stanford Children’s Health CEO
L. Minor
A. Rubin
School of Medicine
Stanford Health Care
T. Quertermous* CV Med
J. Ford* Oncology
Dean
President and CEO
GenePool Biobank
Cancer Institute Genomics Programs
Chief Cancer Genetics
E. Ashley CV Med
L. Boxer
A. Butte
M. Cho
L. Hudgins
J. Merker
K. Ormond
Hematology
Pediatrics
Pediatrics
Pediatrics
Pathology
Genetics
Co-director Clinical Genomics Service
Institute for Inherited CV Disease
Vice Dean
Chief Division of Systems Medicine
Center for Biomedical Ethics
Chief Medical Genetics
Co-director Clinical Genomics Service
Genetics and Genomics Counseling Program
I. Schrijver
M. Snyder
Pathology
Genetics
Molecular Pathology Laboratory
Chair Genetics
Director Center for Genomics & PM

• 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):
– Heritable cancer predisposition
– Heritable cardiovascular disorders
– Pediatric syndromes
– Familial adverse drug reactions or sensitivity

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
Biocurator
Genetic
Counselor
Treating
Team
MP/MG
Analysis
Team
Outside
Faculty
Expert (prn)
Establish questions being posed by patient and treating team
• Genetic?
• Candidate variants and analysis approach
• Clinical use

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)

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

Variant verification by orthogonal method
• Segregation analysis
  
  
Genomics Review Groups
• Genomics Service
• Treating Team
• Content expert
Curation meeting and draft report
Pediatrics
Cardiovascular
Oncology
Pharmacogenomics

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

• 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

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

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.

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.

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.

• Genome and exome analysis for heritable disease
• Tumor/normal sequencing analysis
• RNA sequencing analysis
• Unix commands and basic scripting

End