6.

1 Presymptomatic Genetic Testing

Eedy Mezer, MD; and Alex V. Levin, MD, MHSc, FRCSC

Learning Objectives
1. To understand the issues to consider when addressing a request for predictive (presymptomatic) testing for
genetic disease, such as the ability to treat the disease, the value added for patients by knowing their status
as affected or not, and the value added for society by this knowledge and the potential harms
2. To appreciate the ethical concerns created by predictive testing for genetic disorders in children, in
particular, respect for the autonomy of the child
3. To understand the uncertainties in predicting patient affectation status due to the limitations of currently
available clinical and laboratory tools
4. To appreciate the personal and social potential implications of molecular genetic testing for asymptomatic
children

Case
A 3-year-old boy is brought to the eye clinic by his parents. The child has no apparent eye problem. His 40-year-
old father has retinitis pigmentosa (RP) with onset at approximately 20 years old when he experienced decreased
night vision. The father now has much reduced peripheral vision, although his straight-ahead vision is still normal.
Family history reveals three other affected family members, with a pedigree suggesting autosomal dominant
inheritance. The parents ask, "Will our son get RP?"

Questions
1. What are the considerations about the predictive test?
2. What are the considerations about the disease?
3. Are there potential harms from predictive testing?
4. Are there special considerations for children?
5. Is there policy or empirical research to guide the clinician?
6. How can clinicians best proceed in a non-directive fashion?

Discussion
Q1. What are the considerations about the predictive test?

When considering predictive testing, consider whether the request is feasible and indicated. If no test is available
that predicts future affectation, then the issue is moot. If treatment or prevention is available, such as in cases of
breast and ovarian cancer, retinoblastoma or hypercholesterolemia, then predictive testing is indicated. Testing is
accomplished in various ways for different diseases: clinical examination, ancillary testing or gene testing. Tests
have different sensitivity and specificity. Variable expression and penetrance of genetic disorders may render even
the most specific and sensitive test less powerful. The presymptomatic period may be variable.

In RP, the electroretinogram is often abnormal before clinical examination. Some genes have been identified.
Expression, including age of onset, is variable, and non-penetrance is occasionally observed. Results are most
difficult to interpret in the presymptomatic period. For example, a mild change in the electroretinogram could
indicate that the person will be affected or will be an asymptomatic carrier.

Q2. What are the considerations about the disease?

When a genetic disease is treatable or preventable, predictive testing may be justified.1 In many countries,
neonatal testing for hypothyroidism and phenylketonuria occurs even without specific consent because the societal
benefits of testing outweigh the minimal testing risks. In such diseases, particularly when urgent treatment may
have definitive benefits or when knowledge of affectation status may help to prevent serious disease, there may be
an indication to test with the consent of substitute decision-makers rather than waiting until a child is old enough
to make his or her own autonomous decision. Issues may also arise if parents refuse testing of their child that is
medically indicated2 or if there are other family members who might benefit from testing. In the latter case,
discussions with the family about the sharing of information should be conducted, and if permission is denied,
multidisciplinary efforts may be made to explore the underlying motivation for the refusal, with the hope of
negotiating an outcome that will be beneficial to all.

For untreatable diseases, the benefits may be less certain — both positive and negative results may elicit stress,
depression and anxiety, especially when no therapeutic intervention for diseases is available.3 There is currently no
cure for RP. However, there may be therapeutic benefits to testing. We found that affected individuals with
choroideremia or RP and their unaffected relatives had positive attitudes toward predictive testing, citing the
potential for future treatment, accurate diagnosis, earlier diagnosis and carrier identification.4

Q3. Are there potential harms from predictive testing?

There are risks to testing either positive or negative for an adult-onset disorder. Testing positive for an adult-onset
untreatable disease has been reported to lead to depression (and even suicide), social discrimination,
discrimination by insurance companies or other third parties and, for affected children, undesirable child-rearing
practices such as limiting educational options. Testing negative is generally considered favourable, but may also
lead to feelings in the patient of guilt for not being affected like other family members. Persons testing negative
may also feel disappointed, realizing that they cannot fulfill plans, such as travelling more, that arose when they
believed that they would test positive.5 An additional problem in some cases from predictive testing, regardless of
whether the results are positive or negative, is the potential incidental unexpected finding of non-paternity.

Q4. Are there special considerations for children?

One must balance the child's present and future autonomy and privacy rights with parental interests. Would the
child make the same decision if he or she had the ability to do so independently? As there are potential harms to
predictive testing, it is prudent to allow children to exercise choice in a measure appropriate to their level of
development and experience of illness and treatment.6 For children who are incapable of making their own health
care decisions, parents or legal guardians generally have the legal authority to act as surrogate decision-makers,
although health care providers must ensure that decisions are made in the best interest of the child.7 In the
absence of a clear therapeutic benefit, the health care team must educate parents as to the risks and benefits of
predictive testing that may not have been considered.

Q5. Is there policy or empirical research to guide the clinician?

The Canadian Paediatric Society as well as the American Academy of Pediatrics recommends joint responsibility of
physicians and parents to make decisions for very young patients in their best interest. Ethical issues regarding
genetic testing of children are well discussed, with Huntington disease often used as the paradigm.5,8 The 1994
Working Party of the Clinical Genetics Society in the United Kingdom wrote: "[Predictive genetic testing of children]
should generally not be undertaken... [however,] for some disorders there is insufficient evidence to recommend
for or against... Despite our judgment that it is wise to avoid predictive tests in childhood... if the child stands to
gain some health benefit from predictive testing, then it is obviously good practice to make the testing available."1
Several studies have reported the attitudes of physicians, RP patients and their relatives regarding predictive
testing. Clark reported that 15 per cent of pediatricians opposed predictive testing while 50 per cent of geneticists
were similarly opposed, suggesting that physicians more familiar with the risk-benefit ratio may better perceive
the potential harms.1 We found that more unaffected individuals (67 per cent) supported prenatal testing for
autosomal dominant RP than did affected patients (44 per cent).4 Psycho-emotional distress was reported in 57 per
cent of affected adults and their family members in recollecting their own predictive testing as children.4 Furu et al.
found that only 20 per cent of patients with RP and their relatives recommended testing children.9 Pawlowitzki et
al. reported that 61 per cent of patients with RP perceived potential dangers in molecular diagnostics, but 90 per
cent also perceived potential advantages.10

Q6. How can clinicians best proceed in a non-directive fashion?

Before deciding to proceed with predictive testing for autosomal dominant RP or other genetic disorders, genetic
counselling is recommended so that families and children are optimally informed of the potential risks and benefits
and expectations are adjusted accordingly. Adults may choose not to have genetic testing. If there is no urgency
and no identifiable therapeutic benefit to testing, it may be wise to defer the testing of children to an age when the
child can more actively participate in decision-making. Counselling after testing is also essential, in particular to
screen for adverse reactions. Extrapolation from the literature on genetic disorders may not be appropriate for
patients with RP because other illnesses may carry different inheritance patterns, rates of progression and risks for
morbidity and mortality.

The Case
The ocular genetics counsellor spoke with the parents of the 3-year-old boy and explained the potential risks and
benefits of presymptomatic testing and the lack of known therapeutic or preventative interventions for RP. The
child was reportedly entirely asymptomatic. With this information, the parents decided that there was no need for
predictive testing.

References
1. Clarke A. The genetic testing of children. Working Party of the Clinical Genetics Society (UK). Journal of
Medical Genetics 1994; 31(10): 785–97.
2. Murphy T and Lappé, M. Justice and the Human Genome Project. University of California Press; 1994.
3. Clarke A. The genetic testing of children. Journal of Medical Genetics 1995; 32(6): 492.
4. Mezer E, Babul-Hirji R, Wise R, Chipman M, DaSilva L, et al. Attitudes regarding predictive testing for
retinitis pigmentosa. Ophthalmic Genetics 2007; 28(1): 9–15.
5. Wiggins S, Whyte P, Huggins M, Adams S, Theilmann J, et al. The psychological consequences of predictive
testing for Huntington's disease. Canadian Collaborative Study of Predictive Testing. New England Journal of
Medicine 1992; 327(20): 1401–5.
6. Hellmann J. In pursuit of harmonized values: patient/parent–pediatrician relationships. In: Lynch A, editor.
The “good” pediatrician: an ethics curriculum for use in Canadian pediatrics residency programs. Toronto:
Pediatric Ethics Network; 1996.
7. Harrison C, Kenny NP, Sidarous M, Rowell M. Bioethics for clinicians: 9. Involving children in medical
decisions. CMAJ: Canadian Medical Association Journal 1997; 156(6): 825–8.
8. Canadian Paediatric Society. Guidelines for genetic testing of healthy children. Paediatrics & Child Health
2003; 8(1): 45.
9. Furu T, Kaariainen H, Sankila EM, Norio R. Attitudes towards prenatal diagnosis and selective abortion
among patients with retinitis pigmentosa or choroideremia as well as among their relatives. Clinical Genetics
1993; 43(3): 160–5.
10. Pawlowitzki IH, Ruther K, Brunsmann F, von Gizycki R. Acceptability of prenatal diagnosis for retinitis
pigmentosa. Lancet 1986; 2(8520): 1394–5.