ests based on DNA technology are increasingly
becoming available and have found tremendous applications in clinical
practice. These tests play an important role in diagnosis of the
disease, carrier detection and pre-symptomatic as well as prenatal
diagnosis. DNA based tests are not only technically challenging, but
also present many ethical dilemmas with regard to the indications,
interpretation and implications for the patient and family. One such
ethical issue that needs to be addressed is genetic testing of children.
It is beyond doubt that the testing which can make a
difference in the management of a patient in the immediate future is
essential, whatever may be the age of the patient. However, the
situation in many clinical scenarios is different and complex, e.g., the
request of parents of a child with Hemophilia A or Duchenne Muscular
Dystrophy to test their 7-year-old daughter for carrier status of the
disease. They might argue that they are anxious to know her carrier
status, though it will not be of any significance to her till she
attains reproductive age and wishes to start her family. On the
contrary, the request of a father with multiple endocrine neoplasia II
to test his children for mutation in RET oncogene is justified as there
is a 50% chance for each of his offspring to inherit the mutation.
Medullary thyroid carcinoma has been reported as early as by 3 years of
age in carriers of RET gene mutation. Knowing the carrier status
can help in planning prophylactic thyroidectomy. Another example that
can be considered is the request from a family of Huntington disease to
test their children for the mutation. At present there is no treatment
which can change the course of the disease even when detected
pre-symptomatically. Testing for such untreatable, late onset disease in
children has many ethical, legal and psychological implications. Hence
the issue of genetic testing in various situations has to be assessed
from the perspectives of the child, the parents and the geneticists.
Issues to be Discussed While Testing Children
Benefits and harms of testing
As with all forms of investigations, DNA testing also
has its own benefits and potential harms.
Potential benefits
Medical benefits: DNA testing plays a major role
in arriving at definitive diagnosis in diseases such as spinal muscular
atrophy, Friedreich ataxia, Fragile X syndrome, Leber optic atrophy,
Leigh disease. A confirmed diagnosis helps with counseling and offering
prenatal diagnosis to prevent recurrence in the family. Accurate
diagnosis is necessary to predict the prognosis of a condition,
especially if there is genotype-phenotype correlation. In Myotonic
dystrophy, severity of the disease correlates with the number of
trinucleotide repeats.
Identifying patients with increased susceptibility to
diseases such as cancer by molecular testing helps in surveillance. This
makes pre-symptomatic diagnosis possible and provides adequate time to
take steps for preventing the progression. In MEN II, prophylactic
thyroidectomy protects against medullary thyroid cancer. In a child
diagnosed with unilateral retinoblastoma, adequate surveillance is
needed to prevent involvement of the other eye if the child is a germ
line carrier of RB1 mutation gene. Similarly, unnecessary and
unpleasant procedures such as colonoscopies in familial adeno-matous
polyposis can be avoided if the genetic test is reported to be negative.
Effective measures can be instituted to modify the course of a disease
if there is clarity in the diagnosis. Using appropriate drugs in
familial hypertrophic cardiomyopathy can prevent arrhythmias. Dietary
restrictions have been beneficial in diseases such as familial
hyperlipidemia [1].
Psychological issues: The report can reduce the
uncertainty and offer emotional relief if negative. A positive result is
also helpful in preparing for the future as in planning education,
managing finances and allows time to adjust and avoid emotional
problems.
Reproductive issues: DNA tests may not directly
benefit the tested children as it will only be useful in reproductive or
family planning decisions. But such testing can be utilized by parents
to undergo prenatal diagnosis or consider other reproductive options to
avoid recurrence of the disorder in the family.
Potential Harms
Genetic tests may prompt further investigations and
unnecessary treatments with no proven benefits thus causing distress and
escalating the cost. A child found to be unaffected runs a risk of
rejection by the family, especially when many other members are
affected. A positive test may cause unwarranted anxiety about the
possible early signs of the disorder before any genuine manifestations
actually set in. Testing at an early age deprives the child’s right to
decide about pre-symptomatic diagnosis as an adult. Revealing the
results can impair the self-esteem and lead to discrimination in
education, employment, insurance etc. The reports can adversely affect
the relationship with future partners and lead to coerced decisions.
Decision Making Capacity of the Child
Consent for any test requires competence to make
independent decisions after completely understanding, communicating and
reasoning out. Decision-making capacity is not entirely dependent on
age, with some children having attained this ability by 12 or 14 years
of age. Therefore it is important to individualize each case and assess
the capabilities of the child in concern.
Advocating on Behalf of the Child
One should evaluate whether a request made by parents
for a particular test is appropriate after considering the relative
benefits and harms to the child. It is the major responsibility of the
geneticist to see that the interests of the child get priority.
Psychological and Emotional Effects on Child
It appears logical that genetic testing is likely to
have psychological effects on the child. However, studies till date have
not demonstrated any impact on the emotional state with either the
carrier or predictive testing of children. There seems to be no
significant effect on the child’s self-perception, self-image or
self-esteem [2]. However, more research to evaluate the impact of
genetic testing using more sensitive and appropriate assessment tools to
detect changes over time is needed.
Types of Genetic Testing
Diagnostic Testing
DNA based tests have an important role in diagnosis
of patients as these are the confirmatory or the only diagnostic tests
available for some genetic disorders. Testing for dystrophin gene
deletions is now the preferred confirmatory investigation for Duchenne
muscular dystrophy when clinical signs and symptoms suggest the
diagnosis. Similar is the case of spinal muscular atrophy, Friedriech
ataxia, Fragile X syndrome and many more monogenic disorders. In other
diseases such as sickle cell anemia, hemophilia and thalassemia, though
the diagnosis can be made by other investigations, genetic testing is an
important additional option as it makes prenatal diagnosis possible. DNA
based diagnosis plays an important role in the management of cystic
fibrosis, especially when the sweat chloride test is equivocal.
Pharmacogenetic testing for choosing the safest drug and its dose can be
ordered whenever needed and has the same legal and ethical implications
as that of any other diagnostic test. Though genetic tests for
conditions such as disorders of sexual differentiation are very
important in establishing the etiology and initiating appropriate
management, they are likely to have major emotional and social impact on
the tested child as well as the entire family. As diagnosis of disorders
of sexual differentiation is a medical and social emergency, use of DNA
based and other genetic tests in a neonate or child has the same
implications as any other type of diagnostic tests [3]. Genetic tests
help in counseling and prenatal diagnosis without causing any harm to
the family [4].
Carrier Testing
This type of testing is usually requested when a
relative is affected with an autosomal recessive or an X-linked disease
or when parents are carriers. Testing may allow the carriers to be well
prepared to choose their partners and take appropriate reproductive
decisions. There is consensus among geneticists and pediatricians that
children should not be tested for carrier status. However, the evidence
that such testing causes any emotional or psychological harm is weak.
Presymptomatic Testing
For early onset disorders: It would be prudent to
test children for diseases which have an early onset or for conditions
wherein the early institution of preventive and intervention measures
can affect the prognosis. A good example would be juvenile
hemochromatosis which is caused by mutations in any of the two genes HFE
2 (90% of cases) and HAMP (10% of cases). As the disease is
inherited in an autosomal recessive manner, each sibling of an affected
individual has a 25% chance of being affected. All the family members of
an affected individual should be tested for the mutations identified and
be followed from early childhood with annual ferritin and transferrin
iron saturation. Treatments such as regular phlebotomies can prevent or
reverse many of the complications from organ damage if the disease can
be detected early [5]. Similarly, pre-symptomatic diagnosis of Wilson
disease and retinoblastoma in childhood greatly helps in medical
management of at risk child. This is also the case with RET
mutation in the offspring of a parent with MEN II.
For late onset disorders: Pre-symptomatic
diagnosis of each of the adult-onset conditions presents a different
sort of complexity. While it can help in planning for the future,
availing life insurance, and making reproductive decisions, testing for
conditions such as Huntington disease are known to pose many
psychological, ethical and legal dilemmas. The pre-symptomatic testing
for late onset, untreatable disorders like Huntington disease and
Spinocerebellar ataxias even in adults need pre-test counseling and a
period of decision making. Huntington disease guidelines recommend
against pre-symptomatic testing of children [6]. However, testing an
adolescent for gene associated with a 100% risk of colon cancer or an
18-year-old girl with a family history of breast cancer can provide
relevant information to help surveillance and take preventive measures.
Testing for Balanced Chromosomal Translocation
Testing for balanced chromosomal translocations is
purely of reproductive significance, and is probably best avoided during
childhood. Potential harms are the psychological consequences with
stigmatization as having undesirable characteristics, genetic
discrimination and adverse effects on self-image.
Cancer Susceptibility Testing
Requests for such tests usually come from parents who
are carriers of a cancer susceptibility gene or had cancer as a child to
know the risk of second malignancy. Scientists may seek such tests to
identify children at increased risk of primary or secondary malignancies
to enter them into research protocols. The fact that most cancers have
multifactorial etiology and genetic susceptibility accounts for a small
percentage of cancers complicates testing. In some forms of familial
cancers, genetic testing of children or adolescents is justified as it
offers effective prevention or early diagnosis by surveillance. In
familial adenomatous polyposis, genetic testing can identify children in
the families who are not at increased risk and thus be relieved of the
burden of annual colonoscopies. Although prophylactic resection of the
colon is usually done after 16 years, screening with annual
sigmoidoscopies beginning by 10 years allows for early removal of polyps
and careful follow up. Genetic testing of childhood survivors of
unilateral retinoblastoma is effective as carriers of the altered RB1
gene have a 50% chance of developing a secondary cancer,
identification of whom can aid in surveillance [7]. For some conditions
in which early interventions in childhood will definitely lead to
favorable medical outcome, testing can be done without considering the
minor’s right to decide in future.
On the other hand, there seems to be no justification
for childhood testing in certain familial cancers. Inheriting a mutation
in BRCA1/2 gene confers almost 80% risk of developing breast
cancer and a child of an affected parent has a 50% chance of inheriting
a mutated copy. But currently there is no justification for BRCA
testing in children, as there are no methods effective in early
detection or prevention of cancer and there is no clear role for
prophylactic surgery in children. Recommendations state that BRCA 1/2
testing should not be available to children with or without their
parents’ consent as it carries substantial risks for psychological,
familial and social well-being of those tested [8]. In case of Li-Fraumeni
syndrome, which is a familial cancer susceptibility syndrome, screening
a child for p53 mutation is controversial. There are no effective
screening methods available apart from the regular physical examination
and immediate investigation of symptoms and these can be done even
without genetic testing [9].
Newborn Screening and Prenatal Diagnosis
Though newborn screening programs have been in place
for over five decades in developed countries, they are still in the
infantile phase in India. As the number of conditions covered have gone
up to 30 and new technologies are being incorporated, there is a
pressing need to address the ethical issues and their impact in future
[10].
Effectiveness of newborn screening for disorders such
as phenylketonuria where the benefits of early treatment clearly
outweigh the risks has been proved beyond doubt [11]. There are no
ethical or legal dilemma about including such disorders in the screening
panel. Newer techniques such as tandem mass spectrometry, genomic
screen, microarray, next generation sequencing are likely to reveal
disorders with uncertain natural history and novel genetic variants with
unknown significance, thus paving the way for fresh controversies [12].
Carrier status of neonate for recessive conditions such
hemoglobino-pathies and cystic fibrosis are also expected to be
diagnosed more often and there is a consensus that this should be
reported to parents keeping in mind the future recurrence risk. Although
most of the newborn screening programs provide information to the
parents, these are usually complex to understand, incomplete and at
times misguiding. This leaves the family clueless about the diseases
covered, their natural course, therapeutic options and the costs
involved.
In India there are no well-defined population-based
screening programs though newborn screening tests are being done on a
pilot basis. A written consent is not mandatory and tests are offered
unscrupulously by private laboratories. Some screening panels include
more than a hundred rare disorders many of which are untreatable. There
is also a dearth of experts who can interpret these reports and advice
appropriate management. Confirmatory tests and medications as well as
special diets required to manage the disorders are not easily available.
There are no uniform guidelines for storage and disposal of dried blood
samples which can be very valuable in program evaluation and research.
Thus it is important that as newborn screening takes its root in India,
appropriate guidelines are formulated and well regulated screening
services are provided.
Commercial testing
With the increased availability of commercial/direct
to consumer testing, there is emerging concern that the genetic testing
of children may be ordered by parents without involving the health care
personnel or the child in decision making. Information and counseling
regarding appropriateness of the test, benefits and harms may not be
disseminated adequately. These concerns apart, people may prefer
commercial testing because of the autonomy and anonymity it provides in
matters such as availing life insurance. Such testing may also be
preferred by people who are concerned about a particular condition but
are for some reason unable or unwilling to obtain testing through the
normal routes. There is no assurance that corporations will carry out
the tests after considering the likely age of onset of the condition. As
these tests are available over the counter there will be no one
independently advocating on behalf of the child. The American Academy of
Pediatrics and American Academy of Medical Genetics strictly discourage
direct-to-consumer and home kit genetic testing of children [13].
Conclusions
The implications of genetic testing in children are
similar to any other diagnostic investigation. However, there are many
issues unique to childhood testing for genetic disorders that needs to
be addressed before applying them in this age group. There is no dilemma
in applying the test in children when benefits are very clear. These
tests can confirm the diagnosis, forecast a prognosis and help formulate
a treatment plan. Molecular tests also play an important role in
providing genetic counseling and prenatal diagnosis to the family. There
is a need to discuss in detail, avoid taking hasty decisions and provide
adequate care to safeguard the interests of the child.
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