GENOMIC MEDICINE
NEW TECHNOLOGIES
NEW ETHICS
John Belmont, MDPhD (jbelmont@bcm.edu)
Twitter: @jwbelmon
May, 2014
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Conflict of Interest
• The Department of Molecular and Human Genetics at Baylor
College of Medicine (BCM) offers extensive genetic laboratory
testing, and BCM derives revenue from this activity
• John Belmont, MDPhD is a member of the Ethics Advisory
Board, Illumina, Inc. – consulting fees are paid to Baylor
College of Medicine
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Objectives
• Recognize the shared features and distinctions between
the new genomic technologies.
• Identify the risks and benefits of genomic testing in
research and clinical practice.
• Understand the national discussion about Incidental
Findings in genomic testing.
BASICS OF INHERITED
DISEASE
5
Genetic Material = Book of Life
• DNA is arranged in volumes – the chromosomes
• Humans are diploid - we get one entire set from each
parent
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Human Chromosomes
Female
Male
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Genes = paragraphs in
the genetic book
• About 21,000 genes
• >3000 genes associated with
recognized diseases
• The remainder can be the
subject of research but not
secure clinical interpretation
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Genetic Code = Alphabet
• Genes are composed of
words made with the genetic
material – the triplet code
DNA->RNA->Protein
• The words are spelled with 4
letters – A
CGT
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Types of gene mutations
Normal:
Put the puppy in the box.
Misspellings:
Put the poppy in the box.
Stops:
Put the [ ]
Deletions:
Put the [ ] in the box.
Duplications:
Put the puppy puppy in the box.
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11
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Positive Family History – Affected Parent
Dd
dd
dd
dd
dd
Dd
dd
Dd
Cardiomyopathy
DOMINANT INHERITANCE
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Transmitted Autosomal Dominant
• Parent affected – variable expression or severity
• Sometimes parental mosaicism
• Point mutations or small insertion-deletions in protein
coding sequences
• Can be copy number variant (CNV) abnormality
• DNA sequencing and gene-targeted CNV analysis
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Positive Family History – Affected Sibling,
Affected Maternal Uncle
Rr
rr
Rr
XrY
rr
Parkinson
AUTOSOMAL RECESSIVE
XXr
XY
XY
XrY
Color Blindness
X-LINKED RECESSIVE
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Autosomal and X-linked recessive
• Often single trait, e.g. motor weakness
• Affected siblings or maternal relatives
• Distinctive populations, endogamy or consanguinity
• Point mutations and small insertion-deletions
• DNA sequencing and gene targeted CNV
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Sporadic – No family history
Tall Stature
Ectopia Lentis
Aortic Aneurysm
Syndrome – gene known or unknown
New mutation – neither parent has the genetic defect
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De Novo Autosomal Dominant
• Typical AD disease but lacking family history
• Sometimes complex medical presentations – ‘syndromes’ –
accompanied by multisystem involvement
• Point mutations, small insertion deletions, structural defects,
and CNVs
• If clinically recognized, then single gene testing
• If large differential diagnosis or known locus heterogeneity then
Gene Panels or Whole Exome Sequencing (WES)
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Summary
• Genetic disorders affect 4-8% of the population
(depending on definition)
• There are >7000 genetic disorders (Online Mendelian
Inheritance in Man - omim.org)
• Clinicians must recognize the patterns genetic disorders
even if they do not immediately make a diagnosis
• Occurrences in close relatives
• Early onset
• Severe end of the clinical spectrum
• Unusual clinical features
TECHNOLOGIES
Single Nucleotide Polymorphism Arrays - SNP
Abnormal signal from the
microarray
22q11 deletion syndrome
DNA deletion
Array Comparative Genomic Hybridization
Raw
Normalized
Combined
MECP2
clones
1
0
-1
1
0
-1
1
0
-1
Karyotype vs microarray
• Karyotype resolution 5-10 megabases (Mb) -> 2-5% of
patients with multiple congenital anomalies or
unexplained intellectual disability
• Microarray can detect deletions and duplications 1000-
fold smaller down to 5-10 kilobases (kb) -> 15-20% of this
same patient population
• SNP arrays give information about consanguinity and
ancestry
SNP Array Ancestry – Non-Hispanic White
SNP Array Ancestry - Hispanic
Nextgen sequencing
• Whole Exome Sequencing (WES) by
targeted capture
• Whole Genome Sequencing (WGS)
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Genes are organized into coding
segments called exons
Exome
Exome Technology
Attach single molecules to flow cell
Bridge amplify to form clusters
1.5 billion reads per flow cell
100 bp reads -> 300 Gb per lane
Sequencing By Synthesis
Base calling
TGCTACGAT
Consecutive cycles
The identity of each base of a cluster is read from stacked sequential images
Interpretive Bioinformatics
Data QC
Likely Disease
Causing
Alignment to the
reference genome
Phenotype
Integration
Variant
calling
Filter for common and
non-pathogenic variants
Possibly Disease
Causing
Incidental &
Pharmacogenetic
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There are different kinds of gene
sequencing
• Whole Genome
• Exome
• RNA-seq
• ChIP-seq
• Methyl-seq
All these
methods
generate
identifiable data
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DNA is Transcribed into RNA which is then
Translated into Proteins
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RNA-Seq
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ChIP Seq
Indications for WES/WGS
ACMG Policy Statement 2012
• The phenotype or family history data strongly implicate a genetic
etiology, but the phenotype does not correspond with a specific
disorder for which a genetic test targeting a specific gene is available
on a clinical basis
• A patient presents with a defined genetic disorder that demonstrates a
high degree of genetic heterogeneity, making WES or WGS analysis
of multiple genes simultaneously a more practical approach
• A patient presents with a likely genetic disorder but specific genetic
tests available for the phenotype have failed to arrive at a diagnosis
• A fetus with a likely genetic disorder in which specific genetic tests
available for that phenotype have failed to arrive at a diagnosis.
* Taken from the ACMG Policy Statement
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“Medically Actionable”
• Finding with direct clinical utility based on
established guidelines and/or medical literature
• Availability of treatment or established guidelines
for disease prevention
• Unrecognized secondary diagnosis: Marfan, NF1,
NF2
• Preventable disease: HNPCC, BRCA1,2
Lessons for Clinical Use of WES
• Significant need for diagnostic approaches to
undiagnosed patients
• Many etiologies are already described
• Move from single gene model to comprehensive approach
• Clinical utility for adult and pediatric
• Opportunity for disease discovery
Challenges of Whole Exome
Sequencing
• Laboratory/Interpretation challenges
• Counseling challenges
• Focused/expanded report
• Incidental findings
• Opt-in/Opt-out
• Understanding patient and physician preferences
over time
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Incidental Findings
• American College of Medical Genetics and Genomics (ACMG)
2013 – (http://goo.gl/C888BY)
• “results that are not related to the indication for ordering the
sequencing but that may nonetheless be of medical value or utility to
the ordering physician and the patient.”
• 56 genes that might lead to medically actionable results
• Presidential Commission for the Study of Bioethical Issues
2013 – Anticipate and Communicate
• ACMG – April 2014 – Patients may opt-out at the time that they
consent for WES/WGS
• Autonomy - “the right not to know” – Adorno 2004
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Bioethics Commission on Incidental Findings: Anticipate
and Communicate http://bioethics.gov/node/3186
• Practitioners should inform potential recipients, in any setting, about the possibility
•
•
•
•
of incidental or secondary findings, and if and how those findings will be
disclosed, before the start of a test or procedure. Informed consent and open
communication between providers and potential recipients is essential.
Professional representative groups should develop guidelines that categorize
findings likely to arise from each diagnostic modality, and develop best practices
for managing them.
Federal agencies and other interested parties should fund research to keep
abreast of the rapidly evolving types and frequency of findings; potential costs,
benefits, and harms; and recipient and practitioner preferences about incidental
and secondary findings.
Public and private entities should prepare materials and enhance education of all
stakeholders, including practitioners, institutional review boards, and potential
recipients about the ethical, practical, and legal considerations raised by
incidental and secondary findings.
There is a need – based on justice and fairness – not just for a privileged few but
for all individuals to have access to information and the guidance needed to make
informed choices about what tests to undergo, what kind of information to seek,
and what to do with information once received. Affordable access to care and
quality information about incidental and secondary findings, before and after
testing, can be potentially lifesaving.
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Approaches to Incidental Findings
• Mask raw sequence data so that only disease-related
genes are analyzed
• The lab may analyze all data but have a formal policy of
reporting only disease-associated genes
• Delineate the genes that may be analyzed for medically
actionable IF and then allow the patient to opt-out
• Inform patients in advance of testing and report all
medically actionable IF
Summary
• Strong interest in whole exome testing
• Diagnose rare conditions and common conditions
• Early evidence of clinical utility and cost-effectiveness
• Reporting of non-phenotype findings can be challenging
• Expand phenotypic spectrum of many disorders
Clinical Whole Exome Sequencing (WES)
Sign-Out Conference
http://www.bcm.edu/geneticlabs/index.cfm?PMID=21319
Tel: 1-800-411-GENE / Fax: 713-798-2787
e-mail: genetictest@bcm.edu
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ETHICS CONSIDERATIONS
IN GENOMIC RESEARCH
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Ethical Genomics Research
• Potential BENEFITS
• Increased general knowledge about specific questions
related to microgravity and other health consequences of
manned space flight
• Increased knowledge about personal health risks
• Specific diagnosis of an unsuspected genetic disease
that leads to preventive treatment
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Ethical Genomics Research
• Potential RISKS
• The primary risks involved in genetic research are risks
of social and psychological harm, rather than risks of
physical injury
• Genetic studies that generate information about subjects'
personal health risks
• Could provoke anxiety and confusion
• Damage familial relationships
• Uncover unwanted information about heritage and ancestry
• Compromise the subjects' insurability and employment
opportunities
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Confidentiality and Privacy
• Individual genome sequences are unique and therefore
uniquely identifiable
• Genome sequence placed in the public domain, may
enable others to infer health information about the
individual and his/her relatives
• Genome sequence data can uncover unwanted information
about heritage, ancestry, and family relationships
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Different Levels of Confidentiality and
Privacy Are Possible
• The study may retain genome sequences and not
allow any data sharing to any third party
• The study may share with qualified third parties
conducting related research
• The study may share the data using a secure server
like the NIH dbGAP
• The study may place the sequence in the public
domain
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Important Questions
• Will the subject have the option to receive individual
genome sequence data?
• Will the investigators interpret the results of the
genome sequence and will that result be disclosed to
the research subject?
• If the genome data are given to research subject will
he/she have the option to decline to receive all or part
of the results? (Right Not to Know)
• If there are medically actionable results will the
investigators provide expert counseling or referral?
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Important Questions
• What assurances can be made about health
insurance, disability, life insurance, and
employment?
• What will be the consequences of withdrawal from
the study?
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Genome are Being Sequenced in Populations
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Genomes Are Here
Consumer
Cancer
Reproductive
Health
Agriculture
Research
Human
Genetics
Forensics
Infectious
Disease
Biopharm
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Thank you!