Navigating the Maze of Genetic and Genomic Ethical and Social Issues - - PowerPoint PPT Presentation

Navigating the Maze of Genetic and Genomic Ethical and Social Issues

Howard M. Saal, M.D. Division of Human Genetics Genomics and Ethics in Research and Medical Decision Making March 12, 2015

Genetic and Ethics

Why do genetic/genomic testing?

• Diagnosis of a genetic condition
• Identify genetic predisposition
• Test for carrier status for a specific disorder
• Prenatal testing
• Testing for identity
• Testing for status of a specific illness (usually

related to malignancy)

Genetic and Ethics

Genetic testing

• Assays designed to provide a “definitive

diagnosis”

• Criteria for testing include

– Positive screening results – Family history – Ethnicity/race – Physical stigmata

Genetic and Ethics

Genetic screening

• Assays undertaken on a population-wide basis to

identify at-risk individuals

• Screening criteria1

– Important health problem – Accepted treatment for a recognized condition – Suitable test or examination – Natural history should be adequately understood – Agreed policy on whom to treat – Cost of case finding should be balanced – Should be a continuing process

Genetic and Ethics

1Wilson JMG, Jungner G. http://whqlibdoc.who.int/phpWHO_PHP34.pdf

Types of genetic tests

• Analyte

– Presence – Quantity

• Enzyme activity
• Chromosome analysis
• Chromosomal microarray
• DNA

– Sequencing – Mutation analysis

Genetic and Ethics

History of genetic testing

• Archibald Garrod described alkaptanuria in

1902

– Analyte – Autosomal recessive – In 1908 Garrod reported pentosuria, cystinuria and albinism as autosomal recessive biochemical disorders

• ABO blood groups described by Karl

Landsteiner in 1900

– 1920s familial nature described

Genetic and Ethics

History of genetic testing

• Tjio and Levan

discovered a reproducible method for evaluation of chromosomes in 1956

• They established that

there were 46 human chromosomes

Genetic and Ethics

Diagnoses of genetic disorders

• Down syndrome - 1959
• Turner syndrome -1959
• Trisomy 13 - 1960
• Trisomy 18 - 1960
• Klinefelter syndrome - 1961
• Cri du chat syndrome - 1963

Genetic and Ethics

Chromosomal Microarray

• Microarray uses special technologies for

comprehensive coverage of the entire genome to detect submicroscopic chromosomal imbalances

• Single nucleotide polymorphism (SNP) microarray is

most commonly used technology today

• High coverage with over 4,000,000 SNP markers

across the entire genome

• Ideal for small deletions and duplications

Genetic and Ethics

Genetic and Ethics

• IUGR
• Cleft palate
• Multiple VSDs
• Dysmorphic

Human Genome Project Completed 2003

• Identify all the approximately 20,000 genes
• Determine the sequences of the 3 billion base pairs

that make up human DNA

• Store this information in databases
• Improve tools for data analysis
• Transfer related technologies to the private sector
• Address the ethical, legal, and social issues (ELSI)

that may arise from the project.

Genetic and Ethics

Single gene disorders and gene sequencing

• 20,000 human genes
• 99.99% of human genes have been identified

and sequenced

• Clinical genetic testing is available for over

2500 different single gene disorders

Genetic and Ethics

Testing for single gene disorders

• Helpful for suspected specific genetic

condition

• Not useful for multiple anomaly disorders with

no suspected diagnosis

• Gene sequencing is not available for all

genetic disorders

• Sensitivity of testing rarely 100%
• Genetic heterogeneity

Genetic and Ethics

Whole Exome sequence: Technology moves on

• Human genome is comprised of 3 billion base pairs
• Human exome encompasses primarily protein coding

genes

– Refers to only the coding portion of the genes – Comprise only 1-2% of the genome – Accounts for 85% of disease causing gene mutations1

• Current technology is whole exome sequencing

(WES)

Genetic and Ethics

1Choi et al, PNAS, 106:10196, 2009

• Genetic and Ethics

Genetic and Ethics

Creative Commons, 2012

Genetic and genomic testing and screening

• Genetic/genomic testing is usually a one time event
• Genetic testing has implications for other family

members – Recurrence risks – Potentially affected biologic family members

• Diagnosis of a genetic disorder may not change
• utcome or prognosis
• Genetic testing should always be accompanied by

counseling

Genetics and Ethics

Genetics and Ethics

General recommendations

• Decisions about genetic/genomic testing

should be driven by the best interest of the patient

• Respect autonomy
• Genetic and genomic testing should be
• ffered in the context of genetic counseling

– Need better education of healthcare professionals in genetic counseling

Diagnostic testing

• Use same criteria for testing as other medical

diagnostic evaluations

• Inform patients of benefits and risks of testing
• Get permission for testing
• Consider cost of testing as well

– Genetic tests are expensive – Third party payer coverage is an issue

Genetics and Ethics

Predictive genetic testing

• Usually associated with risk for onset of clinical

manifestations later in life

• May be offered for asymptomatic children at risk

for childhood onset of conditions

• Predictive or predisposition testing for adult onset

disorders should be deferred in children

– Intervention in childhood would reduce morbidity

• r mortality

– Diagnostic uncertainty poses a psychological burden

Genetics and Ethics

Disclosure

• Results disclosure to family

– Ideally should address disclosure issues prior to genetic testing

• Who owns the results

– Genetic information belongs to the patient being tested – Encourage parents or guardians to inform their child of the test results at an appropriate age

Genetics and Ethics

Genetic Testing

American College of Medical Genetics and Genomics ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing

Robert C. Green, MD, MPH, Jonathan S. Berg, MD, PhD, Wayne W. Grody, MD, PhD, Sarah S. Kalia, ScM, CGC, Bruce R. Korf, MD, PhD, Christa L. Martin, PhD, FACMG, Amy McGuire, JD, PhD, Robert L. Nussbaum, MD, Julianne M. O’Daniel, MS, CGC, Kelly E. Ormond, MS, CGC, Heidi L. Rehm, PhD, FACMG, Michael S. Watson, MS, PhD, FACMG, Marc S. Williams, MD, FACMG, Leslie G. Biesecker, MD

Genome sequencing recommendations

• Defined a list of 57 genes corresponding with

24 disorders that should be analyzed and returned to the ordering physician

• Estimate that 1% of tests will return an

incidental actionable finding

• Excluded returning results of conditions for

which there is no definitive medical surveillance or intervention

Genetics and Ethics

Incidental findings

• Hereditary breast and ovarian cancer
• Lynch syndrome
• Familial adenomatous polyposis
• Hypertrophic cardiomyopathy
• Neurofibromatosis type 2
• Li-Fraumeni syndrome
• MEN type 1
• MEN type 2

Genetics and Ethics

Rationale for reporting

• These are serious disorders
• These are actionable disorders
• Do not recommend reporting for disorders for

which no intervention is currently available

– Huntington disease – Alzheimer disease

Genetics and Ethics

Responses to ACMG recommendations

• Patients decisions and right not to know

– No informed consent to search for a deliberate search for the incidental findings – Ethically and legally, the clinician has the core fiduciary duty to respect the patient’s right to decide what testing to undergo and what information to receive

• The child’s right to limits on testing

– Reverses the standard of predictive testing for adult onset disorders in children

Genetics and Ethics

Wolf SM et al, Science 340:1049-1050, 2013

Next Generation Whole exome sequencing (WES)

• Diagnosis of extremely rare and possibly

unique genetic disorders

– Diagnostic yield increased by 30%

• Costly
• Tedious

– Technical aspects are straightforward – Bioinformatic resources are limited – Analysis of data is time consuming

Genetics and Ethics

Patients should be informed about

• Potential benefits
• Potential risks
• Possibility of no diagnosis being made
• Possibility of a diagnosis being made for a

condition for which there is no known treatment

• Identification of possible variants of unknown

significance

• Possible identification of misattributed parentage

Genetics and Ethics

Genetics and Ethics

Knowledge is Ignorance is Power Bliss

Challenges to guideline development

• Next Generation WES is hampered by

insufficient data from normal individuals to assist with clinical patient data interpretation

• Even if a diagnosis is made, what is the

likelihood that there will be an available intervention?

Genetics and Ethics

Whole Exome and Genome Sequencing Variants of Unknown Significance

• When is a variant of unknown significance

significant?

– Results can lead to unnecessary testing and surveillance – Psychological trauma – Misappropriated reassurance

• Your are not just testing the patient (child),

you may be testing other family members as well

Genetics and Ethics

Justice

• Obligation to treat all people fairly and impartially
• Should WES be denied for all patients who wish

not to have information regarding unanticipated

• r incidental findings
• Is it appropriate to withhold results of certain

disorders (Alzheimer disease, Huntington disease) if results can impact life choices?

Genetics and Ethics

Genetic testing is expensive

• Chromosome analysis - $900
• Microarray - $3000
• Single gene sequencing - $600-$4000
• Whole exome sequence - $8000-$12,000

Genetics and Ethics

Genetics and Ethics

Discrepancies in healthcare coverage in the United States

• Often the third party payer determine what

genetic tests are covered

• Third party payers often do not cover any

genetic testing

• Many families are faced with huge

deductibles and co-payments

• Protocols for approval of genetic testing are
• ften outdated and randomly determined

Genetics and Ethics

Challenges to guideline development

• Who should be able to order Next Generation

genetic testing?

– Medical geneticists – Neurologists – Developmental pediatricians – Neonatologists – Pediatricians – Family practitioners

• Who should be responsible for genetic

counseling?

Genetics and Ethics

Need for Genetics/Genomics Services

• The new genomic technologies (and the old
• nes) are complex and challenging
• Primary care providers are ill-prepared to

address the role of the new genomics technologies in healthcare and the psychosocial impact on patients and families

Genomics Education

• Inadequate medical and nursing school

curricula related to genetics and genomics

• Practicing physicians have limited training for:

– Understanding implications of genomics in medicine – Interpreting results of genetic tests

• Similar issues seen in nursing training

Genetics and Ethics

Challenges to guideline development

• There is an insufficient number of genetic

counselors to meet the future needs of advancing clinical testing technology

• Medical genetics residency programs need to

enhance current training in genetic counseling

• Need to expand genetics and genomics curricula

in medical schools and residency programs to address the influx of genetic/genomic technology into healthcare

Genetics and Ethics

Genetics and Ethics

General recommendations

• Decisions about genetic testing should be

driven by the best interest of the patient

• Respect autonomy
• Genetic and genomic testing should be
• ffered in the context of genetic counseling
• Adequate training in genetics and genomics

is the responsibility of the entire healthcare community

Genetics and Ethics

Knowledge is Ignorance is Power Bliss