Societal implications of the new genomics: Relevance to medicine; D2C testing

Question 1

Reproductive decision making

Answer 1

e.g. health and fertility

Question 2

Prenatal diagnosis (foetal cells): preimplantation genetic diagnosis (PGD). DS from maternal blood

Answer 2

 At a very early stage, we can now identify individuals at risk for particular disorders. Preimplantation genetic diagnosis: when it’s only divided a few times, can take one cell sequence its DNA for genetic abnormalities. Implant the remaining 7 cells and it will continue to develop normally
 Can also identify genetic conditions (e.g. Down Syndrome) in the foetus for maternal blood cells.

Question 3

Why identify high-risk individuals (risk loci, polygenic scores)? Social implications of newborn genome sequencing?

Answer 3

 Preventative approach to care (proactive vs. reactive).
 Behaviour modulation.
 Symptom awareness
 Likelihood of developing a disease (e.g. BRCA mutations).
 Social implication of newborn genome sequencing
• Babies can’t give informed consent for their genetic data to be out in the public domain.

Question 4

How may genetic advances influence therapeutic care: pharmacokinetics, efficiacy/safety, better clinical trials.

Answer 4

• Genetic variants may influence drug liberation, absorption, metabolism, excretion.
• Efficacy/safety: tailored drug dose per variant, choice of strategy, choice of drug (e.g. TCA vs. SSRI vs. MAOI)
• Better clinical trials: selection of high-risk individuals (rather than infected patients), selection of homogneous patient groups, knowledge about likely drug response (e.g. genetic polymorphisms within genes encoding cytochrome P450 enzymes can be used to predict antipsychotic drug response and to minimise side-effects), and drug*drug interactions.

Question 5

Outline Clustered Regularly-Interspaced Short Palindromic Repeats (RNA-guided, tissue reimplanted, limited utility, CF, SCA). Limitations: ethics, immoral to play or God or immoral to not? Proving causal genetic variations. Animal/cellular models.

Answer 5

• RNA-guided genome editing tool based around components of prokaryotic “Immune system”>
• Tissue (e.g. stem cells from blood) can be removed from patient, gene defect corrected, and tissue re-implanted.
• Again, limited utility for complex polygenic disorders with neurobiological basis.
• Currently in trials for cystic fibrosis and sickle cell anaemia.
o Would “patients” have wanted their genomes edited.
o Is it immoral to mess around with nature?
o Or is it immoral not to, given the possibility of alleviating suffering.
• Other issues
o Proving genetic mutations/variants are causal is very difficult: can be addressed using e.g. animal/cellular models designed via CRISPR
o Animal/cellular models can be developed using CRISPR and used for testing.

Question 6

Optogenetics: neural circuit modulation (Burguiere et al., 2013: mouse genetic grooming, cortico-striatal activity). Limitations: solved with DREADDs.

Answer 6

• Modulation of neural circuits (not single genes) via introduction of genes for light-sensitive receptors.
o See: Burguiere et al. (2013)
o Mouse genetic mutant shows excessive grooming related to reduced cortico-striatal activity.
o Possible utility in humans, e.g. for Deep Brain Stimulation, but issues re brain penetration.
• Issues: difficult to stimulate genes in deep brain regions, solution is DREADDs.

Question 7

Key issues: Infancy large genomics (poor knowledge underlying biology: which variants, epistasis (even monogenic), cellular/physiological/environmental factors). Validity of genetic tests.

Answer 7

o Poor knowledge of underlying biology for complex polygenic conditions.
 Large-scale genetics (genomics) is in its infancy; we currently know relatively little about:
• Which genomic variants influence disorder risk, to what extent and how (“pleiotropy” e.g. SCZ and CHRNA gene association).
• How genetic variants within a person’s genome interact to modify disorder risk (“epistasis”); even for monogenic conditions!
• How the genome interacts with cellular, physiological, and environmental factors to modify disorder risk.
 Genetic tests for complex conditions currently have limited clinical validity and utility (risk quotients).

Question 8

Undermines role of epigenetics

Answer 8

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Question 9

Implications for relatives: differing views on need, disclosure if/how, Fragile X (ovarian failure, degenerative ataxia), repro decision making.

Answer 9

 Relatives may have differing views on need for genetic information.
 Issues related to whether or not to disclose genetic information to relatives, and how.
 Fragile X mutation in proband.
• Increased maternal risk of premature ovarian failure.
• Increased grandpaternal risk of degenerative ataxia.
 Issues related to reproductive decision-making, e.g. if/when/how to have children and if/when/how to get them tested.

Question 10

Irrevocable results

Answer 10

• Possession of risk variant for another disorder?
• Relating to relationships (paternity, extra-marital affairs, etc.)
• Relating to possible future life choices (e.g. likelihood of infertility).

Question 11

Newborn screening: emotional readiness in postpartum period, failure to understand significance of results assoc. with strain on unrelated health services + family dysfunction (Waisbren et al., 2003). Genetic counsellor in ideal world.

Answer 11

 A context in which parents often receive information about disorders they’ve never even heard of, as a result of a test which they may not have been totally educated about. During the best of times, the postpartum period is extremely stressful and parents may not be emotionally prepared for the stressful news about the detection of a potential serious disorder for their newborn. When unprepared for this news at this time, they may not understand the significance of the result and the process of determining if the screening result is true or false. This failure to understand the implications of a positive screening result (whether true or false) is associated with the use of health services unrelated to the tested disorder, and to dysfunctional parent-child relationships. (Waisbren et al., 2003). Given these issues and sensitivities, genomic information would ideally be delivered by a trained genetic counsellor, but this poses feasibility issues in public healthcare due to the need or extensive case preparation, a review of family medical history, and pre- and post-test education and counselling.

Question 12

Individual differences in reactions to data: gender and age.

Answer 12

 Limited evidence (CESAGEN) for gender effects:
• Males tend to react logically and analytically to D2C findings.
• Females tend to react more emotionally and frame with regards to family and friends.
 Possible age effects
• Younger individuals may be less concerned about risk of typically late-onset disorders.
• Older individuals may be less concerned about risk of typically early-onset disorders.

Question 13

Uncertain added value for complex multigenic conditions: prognosis limited, behavioural changes same (exception PKU), ineffective treatment for those w/ strong genetic component (e.g. EO, LOAD)

Answer 13

 Currently, genetic data provides little further useful information than personal/family history of disorder, re prognosis.
 Behavioural changes to minimise disorder risk will be identical in the presence/absence of genetic information.
 Healthy diet (although PKU)/low stress/good sleep routine/high levels of physically and cognitively demanding activities/no smoking, low alcohol consumption.
 Some serious disorders with a strong genetic component (e.g. EO and LOAD) currently have few, ineffective treatment options; limited value in knowing personal risk.

Question 14

Disclosure to other parties

Answer 14

 Possible future requirement to disclose genetic data to insurance companies, employers, schools, etc.
 Possibility of submitting DNA sample to D2C service without consent.
 Possibility of mix-up

Question 15

Possibility of stigmatisation.

Answer 15

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Question 16

Cease and desist for D2C (23andMe, Navigenics): hypertension and prostate cancer disparity, deceptive marketing, 33 state restriction on urge to test fiance’s DNA/

Answer 16

o An investigation of direct-to-consumer genetic testing companies conducted by the US Government Accountability Office found that test results were “misleading and of little or no practical use” (65, p. 4). This investigation included major companies such as 23andMe and Navigenics. Identical samples sent to different companies yielded varied results. For example, a single sample sent to four companies was identified as indicating average, below-average, and above-average risk for prostate cancer and hypertension. The investigation also found several instances of deceptive marketing, including claims that customers’ DNA could be used to create supplements that would cure disease, fraudulent use of celebrity endorsements, and statements that implied that the results were diagnostic. Furthermore, two companies urged a fictitious consumer to secretly test her fiancé’s DNA to “surprise” him despite this practice being restricted in 33 states.