1. Ethical, Legal & Social Issues in Human Genetics
Cinnamon S. Bloss, Ph.D.

2. Why “ethics” or “social impacts” in genetics?
What is the meaning of genetic exceptionalism?

3. Discussion “Food for Thought” Questions
How does personal genetic information affect an individual and society's perceptions of that individual?
How does genomic information affect members of minority communities?
Do healthcare personnel properly counsel parents about the risks and limitations of newer genetic technologies?
How do we prepare the public to make informed choices?
How do we as a society balance current scientific limitations and social risk with long-term benefits?
Who owns and controls genetic information and how will it be used?
Should testing be performed when no treatment is available?
Should parents have the right to have their minor children tested for adult-onset diseases?

4. Overview Why “ethics” or “social impacts” in genetics?
Some historical aspects of genetic testing & technology
Genetic exceptionalism
“ELSI” Program & Human Genome Project
Societal concerns arising from the “New Genetics”
Some of the ‘Biggies’
Privacy and consent
Data sharing and non-discrimination
Incidental findings
Case Studies

5. Some Human Genetics Milestones
1866
Mendel’s theories of inheritance are published
Sir Archibald Garrod describes the autosomal recessive inheritance of albinism (and later other diseases such as cystic fibrosis)
William Bateson describes the autosomal dominant nature of many diseases (e.g., Huntington’s, Marfan’s)
Wilhelm Johannsen coins the term “gene”
Han Winkler coins the term “genome”
Watson, Crick, and Franklin discover the structure of DNA
Lejeune et al. show that Down’s is a chromosomal abnormality
Riis & Fuchs perform the first prenatal sex determination
Jacobson & Barter use amniocentesis for prenatal diagnosis
Huntington’s disease gene is mapped to chromosome 4 (first genetic test)
Cystic fibrosis gene is mapped to chromosome 7
Richard Buckland becomes the first person acquitted of a crime based on DNA
Stephen Fodor builds first DNA “microarray” foreshadowing modern GWAS era
Human genome project is launched
BRCA1 is located; high penetrance nature is responsible for ~½ of all early onset breast cancer and the majority of familial breast and ovarian cancers
1908
1909
1920
1953
1959
1960
1967
These disorders and modes of inheritance also have led to a common fatalistic view among lay people that genes are deterministic and that if one inherits a disease allele, one will inherit an unwanted disorder. This view stands in opposition to more recent notions of the “susceptibility allele”, based in large part on findings from the field of genomics, specifically GWAS, in which
inheritance of a specific genetic variant does not guarantee the emergence of a disease, but merely confers some environmentally and/or other genetic factor mediated probability of
developing a disease.
1983
1985
1986
1989
1990
1994

6. Modern Concepts of “Genomic” Risk & Susceptibility
2000
Human Genome Project complete initial draft of entire human genome
International HapMap Project released genome-wide database cataloging common genetic variation within and across individuals and populations
Identification of complex (i.e., non-Mendelian) disease causing variants
Genetic influences on complex diseases are attributable to common genetic variants (>5% of population)
Variants represent “risk factors” or “susceptibility variants” versus deterministic variants
With technological advances, first genome-wide association study published:
Klein, R.J., et al., Complement factor H polymorphism in age-related macular degeneration. Science, 2005
Over 400 GWAS published identifying over
150 risk variants for more than 60 common
diseases and traits
2004
2005
2009

7. Classic Genetics vs. Genomics
Single gene, Mendelian inheritance
Genotype-phenotype relationship is well understood
Genetic test has (usually) clear clinical utility
CLIA-approved clinical testing available with result report
Carrier testing (CF, Tay-Sachs, errors of inborn metabolism)
Diagnostic testing (Fragile X, neurofibromatosis)
Predictive testing (BRCA1/2, Huntington’s)
Whole-genome/whole exome approaches
SNP testing or high-throughput sequencing
Large amount of information
(includes known disease causing genes + all others)
Gene x Environ interactions, tests now only indicate small changes in risk
Early utility: “Solving” rare genetic diseases, diagnosing recessive conditions by testing entire families, gene discovery
Bottleneck: Interpretation of the genomic data

8. Why ethics in genetics?

9. Growth of Genetic Tests
Beaudet, Nature, 2010

10. Why Ethics in Genetics? Uniqueness of Genetic Information…(?)
Identifying: Genetic information is identifying not only on an individual level but a familial (and parentage) level as well.
Ubiquitous: Identity and genetic status can be gathered from a small amount of material and is permanent rather than transitory information.
Longevity: Genetic samples and data can be kept for indeterminate periods of time.
Predictive: Can be diagnostic, predictive, or provide risk information.
Individual and familial nature: Most genetic information flows between generations. These implications may extend beyond the family to larger groups of closely linked people with common ancestry, for example, indigenous, ethnic or ethno-religious communities.
Shared Information: Genetic information as shared information affects who may be regarded as the 'patient' since it may be the individual as well as the family. This raises unique challenges for individual autonomy and consent as well as the duty to warn and the right not to know.
Informational risks: Genetic information may put individuals, families and communities at risk of discrimination and stigmatization.
Symbolic meaning: Genetic information tends to be regarded as particularly symbolic in part due to its social perception as a human blueprint representing the essence of life.

11. Genetic Exceptionalism
Genetic Exceptionalism vs. Sensitive (Medical) Information
Belief that genetic data require a greater degree of protection than other medical or personal data because of their unique special nature.
Arguments against suggest that other non genetic information have similar qualities, although perhaps less amplified.
“Key findings included the theme that genetic information was much like other medical information and
that all sensitive medical information should be well protected.”
Diergaarde et al., 2007, American Journal of Medical Genetics
While genetic information may not be exceptional, the emotional experience around genetic privacy may be different.

12. Case #1 Case 1: Huntington Disease predictive testing
Mr. F, a 42-year-old man and his 21-year-old son George come to a genetic testing center for advice. George wants to be tested for Huntington disease, a progressive, fatal inherited brain disorder that usually strikes its victims in their 30s, 40s and 50s.
There is a 50% chance that Mr. F has inherited the gene for Huntington disease and, if so, a 50% chance he has passed it along to his son George. Mr. F doesn't yet show symptoms of the disease and he doesn't want to be tested. He prefers to live his life and make decisions without knowing whether or not he has the gene. George, on the other hand, wants to know if he has inherited the gene so he can plan his life accordingly.
If George gets tested and is found to carry the gene for Huntington disease, his father, Mr. F, must also carry the gene. The two men agree that, given their close relationship, it would be impossible for George to keep his test result a secret from his father.
Does George have a right to know whether or not he carries a disease gene even if it interferes with his father's wish not to know his genetic status?
Does Mr. F have a right not to know?
Would you want to know?
(This situation also applies to identical twins where one wishes to know, and the other does not)
Cases courtesy of Dr. Lisa Madlensky

13. ELSI Program and Human Genome Project

14. “ELSI” Program & Human Genome Project

15. What is ELSI?
U.S. DOE and NIH devote 3-5% of their annual Human Genome Project budgets toward “ethical, legal and social issues (ELSI)” surrounding the availability of genetic information
This represents the worlds largest bioethics program
The Idea
Genomics has presented new and complex ethical and policy issues for individuals and society
Programs that identify and address these implications an integral part of the U.S. HGP since its inception
These have resulted in a body of work that promotes education and helps guide the conduct of genetic research and the development of related medical and public policies

16. ELSI, NHGRI & HGP

17. ELSI Issues Fairness in the use of genetic information
Privacy and confidentiality* 
Psychological/behavioral impact
Stigmatization, and discrimination* 
Reproductive issues* & Forensics
Clinical issues (regulation*, education of providers)
Uncertainties (as related to susceptibilities to complex conditions)
Conceptual and philosophical implications (human responsibility, free will vs. genetic determinism)
Health and environmental issues concerning genetically modified foods
Commercialization of products including property rights (patents, copyrights, and trade secrets)

18. Classic Paper

19. Some of the ‘Biggies’ Privacy and consent Data sharing and non-discrimination Incidental findings

20. Privacy

21. Privacy
“Addresses the question of who has access to personal information and under what conditions. Privacy is concerned with the collection, storage, and use of personal information…” (Nass, Levit & Gostin, 2009)
“Defined in terms of a person having control over the extent, timing, and circumstances of sharing oneself (physically, behaviorally, or intellectually) with others.” (Plaza & Fischbach)

22. Privacy as basic human right Valuable because promotes other values
Value of Privacy
Privacy as basic human right
Valuable because promotes other values
Personal autonomy (the ability to make personal decisions)
Individuality
Respect
Dignity and worth as human beings

23. Clinical utility vs. personal utility
Access & “Right” to Genetic Testing
Clinical utility vs. personal utility
Will the test result change medical management?
Treatment, therapy, prevention
Will the result be used for “personal knowledge”?
Cultivate sense of control and understanding
Do patients have a right to their genetic information? Issues of autonomy and privacy?
Health disparities and access: Insurance vs. self-pay (“medical necessity”)

24. Privacy Ethical Issues
Consideration of the whole family vs. a single patient
Right to know vs. rights of relatives to not know
Testing can reveal non-paternity, consanguinity
Can reveal ancestry, heritage personal/family identity
Need participation of multiple family members for interpretation

25. Case #2 Case 3: Parental rights vs children’s rights
…it turns out that the consent form from Case 2 above had indicated the following:
“You may choose to be notified of findings that are discovered in the course of this research project that are not related to Miller Syndrome, but that may impact your own health or the health of family members. By checking the box below, you are indicating that you wish to be notified of such information”
The Greens had indeed checked the box, and so the researchers feel as though they do need to inform the Green family of the BRCA1 finding. The study coordinator who reviewed the initial consent form with the Greens arranges to meet with them and tells Mr. Green that he has incidentally been found to carry a known BRCA1 mutation. Mrs. Green immediately asks “Do Gene or Jeannie carry the mutation as well?”
Typically genetic testing for adult-onset disorders is not available to children, as it would not alter their clinical care until they reach adulthood. Does Mrs. Green have a right to know the BRCA1 status of her children?
The research co-ordinator indicates that she doesn’t feel comfortable disclosing the children’s BRCA information, and refers Mr and Mrs Green to a genetic counselor at a local cancer center. The genetic counselor explains to the Greens the reasons that BRCA testing is not performed on children, and explains that there is a high value placed on the autonomy of the individual to choose when they would like to receive genetic test results. Mrs. Green becomes very angry and says “But you already have the information, and I’m her mother so I’m in charge of her medical care, and I demand that you give me the BRCA information for the children”
Does the genetic counselor have to disclose the information to the Mrs Green? Why or why not?
Does the fact that the BRCA information came to light because of a research protocol (as opposed to routine clinical testing) matter? How would you respond to Mrs. Green?

26. The Internet, Data Sharing, and Privacy
Study using whole genome sequencing for diagnosis
Case: 14-Year-Old Female
Patient knowledge and understanding (not to mention false hope issues…)
Patient’s Blog
“As most of my close friends probably know, I am in a study…to get my entire genome mapped…”

27. Impacts on Communities

28. Informed consent process for clinical genetic testing
Informed Consent Ethical Issues
Informed consent process for clinical genetic testing
Typical genetics consultation: minutes
Includes discussion of test specifications, implications of positive result, negative result, possibility of “variant of uncertain significance”
Genetic counselors, physicians, specialists, staffing
Once you get a result, it can’t be un-known…

29. Genetic Discrimination

30. Non-Discrimination
GINA, 2008

31. CalGINA extends non-discrimination protection to additional areas
Federal GINA provides limited non-discrimination protection in the areas of employment and health insurance
CalGINA extends non-discrimination protection to additional areas
Receipt of emergency medical services and care;
Interests in real property, including sales and rentals (fair housing);
Receipt of services, access to facilities, accommodations, and privileges “in all business establishments of every kind whatsoever”;
Distribution of alcoholic club licenses;
Provision of financial assistance for purchase or construction of housing (mortgage-lending); and
Participation of any state-funded or state-administered activity or programs.

32. Incidental Findings and Return of Results

33. Incidental Findings
A finding concerning an individual participant that has potential health importance and is discovered in the course of conducting research but is beyond the aims of the study.
Wolf et al., 2008, Journal of Law, Medicine & Ethics

35. Examples
an IF on a genomic microarray suggesting a genetic or chromosomal variant of potential clinical importance beyond the variants or genotype phenotype associations directly under study,
an IF of misattributed paternity or parentage in a genetic family study,
an unexpected mass or aneurysm visualized in the course of structural magnetic resonance imaging (MRI) of the brain, and
an unexpected mass at the base of the lung discovered in computed tomography (CT) colonography.

36. Genomic Medicine vs. Research
Since so many genetic conditions are rare, a “clinical” genetic test takes time to emerge from research
Patients/families with rare, poorly understood diseases are often willing research participants
What genetic information goes back to participants?
Requires a well thought-out informed consent process with clear expectations

37. Case #3 Case 2: Incidental findings in genetic research
Gene Green, age 7, was diagnosed with Miller Syndrome (also known as postaxial acrofacial dysostosis), because of his craniofacial features and abnormal limb development. Miller Syndrome usually presents with a recessive mode of inheritance. Gene’s parents are very interested in participating in genetic research to help determine which gene might cause Miller Syndrome. The research protocol includes whole exome sequencing of multiple family members, and Mr. and Mrs. Green sign the consent forms on behalf of themselves as well as on behalf of Gene and his older sister Jeannie (age 10). Samples are provided by all 4 family members.
The research team sequences the whole exomes of all four family members to identify sequence changes that may be causing Miller Syndrome in a recessive manner. In the course of analyzing and characterizing the DNA sequence variants, it is noted that both Mr. Green and his daughter carry a well-characterized deleterious mutation in the BRCA1 gene. BRCA1 mutations confer a highly elevated risk of breast and ovarian cancer in adulthood.
Is the research team obligated to inform the Green family of these findings?
What type of language could be used on a consent form to ensure that research participants are aware of the possibility of incidental findings?
What about participants from older research studies where this possibility was not specifically addressed in the consent form?
Is it ethical to suggest to patients that they will be notified of sequence changes that may impact their health or reproductive decision-making if there is not actually manpower or capacity to do so?
If the results should be disclosed, who should be the one to inform the Greens? The research team? A healthcare provider?

38. Discussion “Food for Thought” Questions
Who owns and controls genetic information and how will it be used?
How does personal genetic information affect an individual and society's perceptions of that individual?
How does genomic information affect members of minority communities?
Do healthcare personnel properly counsel parents about the risks and limitations of newer genetic technologies?
How do we prepare the public to make informed choices?
How do we as a society balance current scientific limitations and social risk with long-term benefits?
Should testing be performed when no treatment is available?
Should parents have the right to have their minor children tested for adult-onset diseases?