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, Kauai10/23/2014

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 typeAverage limit of detection (% allele burden)

Genome sequencing ~20 – 30%Exome sequencing ~20 – 30%NGS-based gene panels 5 – 10%Sanger sequencing 20%Single mutation assay <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 Genomicsat Stanford

Clinical Genomics Efforts at Stanford

Clinical GenomicsService

GenePool Biobank

Basic, Translational,and Clinical Research

Advisory Committee for Clinical GenomicsName 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 ProgramsChief Cancer Genetics

E. Ashley CV Med Co-director Clinical Genomics ServiceInstitute 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 GeneticsDirector 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):– Heritable cancer predisposition– Heritable cardiovascular disorders– Pediatric syndromes – Familial adverse drug reactions or sensitivity

Workflow – 1

Test Request Patient and physicianrequest genome sequencingfor heritable disease throughEMR

Review by GeneticTest Consultation Service• Genetic Counselor• Molecular Pathologist• Medical Geneticist

Analysis TeamMP/MG

Biocurator

Genetic Counselor

Treating Team

Outside Faculty

Expert (prn)

Establish questions being posed bypatient and treating team• Genetic?• Candidate variants and analysis

approach• Clinical use

Workflow – 2

Insuranceauthorization

Patient meets with geneticcounselor• 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

Variant verification by orthogonal method• Segregation analysis

Curation meeting anddraft report

Gen

omic

s Re

view

Boa

rds

Pediatrics

Cardiovascular

Oncology

Pharmacogenomics

Genomics Review Groups• Genomics Service• Treating Team• Content expert

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 ServiceRationale #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 ServiceRationale #2 – The number of misorders for complex

genetic testing is high

Miller CE et al. 2014. Am J Med Genet Part A 164A:1094–1101.

“Approximately 25% of all requests for complex genetic tests assessing germ line mutations were changed following review.”

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

MolecularPathologist

GeneticCounselor

MedicalGeneticist

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/RNA2. Fundamentals of human genetic variation3. Microarrays and analysis of hybridization data4. Sequencing methods5. Heritable genetic disorders6. Acquired mutations in human cancers I: solid tumors7. Acquired mutations in human cancers II: hematopoietic

malignancies8. Pharmacogenomics9. HLA genetics10. 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 2.02. Human genetic variation 2.03. DNA sequence analysis methods I: sequence

databases and files4. DNA sequence analysis methods II: sequence

alignment algorithms5. DNA sequence analysis methods III: genome assembly

and analysis6. Introduction to scripting programming languages7. 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 2.02. Human genetic variation 2.03. DNA sequence analysis methods I: sequence

databases and files4. DNA sequence analysis methods II: sequence

alignment algorithms5. DNA sequence analysis methods III: genome assembly

and analysis6. Introduction to scripting programming languages7. 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