DNA Testing of Asymptomatic Children

[Guest guest]

DNA testing of children who aren't yet exhibiting symptoms (asymptomatic) should

be carefully considered, weighing the risks vs the benefits. Everyone is

different and no issue like this is black-and-white. I thought this article did

a good job of outlining the issues for consideration. Especially the section

below on testing of asymptomatic at-risk patients, insurance/employment, and

children.

http://www.medscape.com/viewarticle/417571

Risks and Benefits of DNA Testing for Neurogenetic Disorders

from Seminars in Neurology

D. Bird, M.D. Departments of Neurology and Medicine, University of

Washington, VA Medical Center and Geriatrics Research Center, VA Puget Sound

Health Care System, 1660 South Columbian Way, Seattle, Washington.

Abstract and Introduction

Abstract

DNA testing for mutations in genes causing neurogenetic disorders is becoming a

common practice in clinical neurology. The tests are highly sensitive and

specific. They are especially valuable in establishing diagnoses in symptomatic

patients. These DNA tests are also used in asymptomatic persons at risk for

genetic diseases who wish to determine whether or not they have inherited an

abnormal gene. There are risks and benefits to such asymptomatic, predictive

testing. A number of complex issues need to be considered including

precipitation of depression, prenatal diagnosis and testing of children, impact

on insurance and employment, legal aspects, possible third-party coercion, and

an understanding of each test's limitations. Therefore, these DNA tests need to

be used with careful clinical judgment and in the context of each individual

patient and family.

Introduction

The past decade has witnessed a new development in the practice of neurology.

Genetic research and technology have provided the knowledge and tools for the

development of highly sensitive and specific DNA tests for neurogenetic

disorders.[1] These tests directly identify mutations in disease causing genes.

The number of diseases available for such testing is expanding at a rapid rate

(Table 1). Such testing may have complex implications for the patient, other

family members, and the broader community. The purpose of this review is to

provide neurologists with a clinical perspective of the risks and benefits of

DNA testing. In clinical practice these genetic testing scenarios can be divided

into two major categories that have different strategies and implications: (1)

testing symptomatic patients or (2) testing asymptomatic " at risk " patients.

Testing Symptomatic Patients

The first scenario involves testing of patients who have symptoms of the genetic

disease. This represents relatively straightforward diagnostic testing with

which all physicians are trained and comfortable. For example, this involves

telling a patient with chorea that a blood test demonstrates the presence of the

Huntington's disease (HD) gene, or telling a patient with muscle weakness that

the test is positive for myotonic dystrophy. These diagnostic situations are

similar to discovering a brain tumor with neuroimaging, meningitis with a lumbar

puncture, or epilepsy with an electroencephalogram (EEG). The major difference

with DNA testing is that the diagnosis has genetic implications for other family

members. The physician must be ready to deal with the ensuing genetic questions

triggered by a positive test (see below).

Diagnosis/Prognosis

DNA-based diagnostic testing can be valuable for many reasons. The most obvious,

is making a specific diagnosis. This is, of course, one of the major aspects of

the practice of medicine. Specific diagnosis is important because it removes

ambiguity and often clarifies prognosis. For example, in a patient with signs of

bulbar motor neuron disease, a positive DNA test for Kennedy's spinobulbar

muscular atrophy (SBMA), eliminates all other potential causes of the

syndrome.[2] Furthermore, it implies a relatively better prognosis and longer

course than the same presentation in a patient with amyotrophic lateral

sclerosis (ALS). Likewise, in a patient with myotonia, a positive test for

myotonic dystrophy eliminates other potential causes such as myotonia

congenita.[3] Furthermore, the longitudinal follow-up of this patient would

direct the physician toward monitoring of factors such as blood sugar,

electrocardiogram (ECG) and slit-lamp examination of the lens.

The evaluation of isolated or sporadic cases with symptoms compatible with or

suggestive of a genetic disease can pose difficult testing decisions. It should

be recalled that sporadic instances of a possible genetic disorder can be

explained in five different ways: (1) an environmentally caused condition that

mimics the genetic disorder (a so-called phenocopy); (2) an autosomal recessive

disorder; (3) a new mutation of an autosomal dominant disease; (4) lack of

penetrance of clinical symptoms in other family members who actually carry the

disease mutation; and (5) false paternity. In such isolated cases, the physician

needs to consider all these possibilities and then make a clinical judgment as

to the desirability of proceeding with genetic testing. Obviously, it would be

valuable to know the results of previous studies indicating the likelihood that

a sporadic presentation of any given syndrome will prove to have a positive

genetic test. Such

information is highly disease specific. Unfortunately, such data for each

disease is either nonexistent or scattered throughout the medical literature. A

developing Internet website that is addressing this issue is

www.geneclinics.org, which presently contains such information for several

neurogenetic disorders.

An example of the testing approach to sporadic cases is that of the hereditary

ataxias. Many isolated patients with ataxia have an acquired or nongenetic cause

such as alcoholism, brain tumor, multiple sclerosis, or a paraneoplastic

syndrome. On the other hand, progressive ataxia can certainly be the result of a

variety of specific genetic disorders. Autosomal recessive diseases often

present as single cases and Friedreich's ataxia, ataxia telangiectasia, and

alpha-tocopherol deficiency are recessive causes of ataxia. Furthermore, Moseley

et al.[4] have shown that about 10% of sporadic cases of ataxia will test

positive for one of the numerous types of dominant spinocerebellar ataxias (SCA)

or Friedreich's ataxia. In addition, most of the dominant SCAs have considerable

overlap in their clinical presentations, such that it is difficult to

differentiate one from the other in a single patient. Therefore, many commercial

laboratories provide a panel of

several DNA tests that can be preformed on an individual case with an

unexplained progressive ataxia without a known acquired cause. The physician

must make a judgment decision concerning the potential value of genetic testing

based on the relatively high likelihood (90%) of a negative test in a sporadic

case and based on the clinical symptoms that may more or less suggest one or

more subtypes of hereditary ataxia. These are not simple decisions, but are

similar to many other diagnostic testing " decision trees. " A similar situation

exists for many other neurogenetic conditions including hereditary neuropathy,

early onset dementia, mental retardation, motor neuron disease, and muscular

dystropy.

Genetic Risks To Relatives

DNA testing also has important genetic counseling implications. Kennedy's SBMA

is X-linked recessive, which has different implications for family members

compared with ALS (which may be nongenetic or occasionally autosomal dominant).

Becker's muscular dystrophy is also X-linked recessive which, again, has

different genetic implications compared with limb-girdle muscular dystrophy (MD)

with which it is often confused.[5] Limb-girdle MD may be autosomal recessive or

autosomal dominant. The discovery of a positive test for an autosomal dominant

genetic disease means that each child of the affected patient is at 50% risk for

also inheriting the disease mutation. Friedreich's ataxia (FA), on the other

hand, is autosomal recessive, and it is now clear that FA can sometimes present

in adulthood.[6] Offspring of patients with autosomal recessive disorders are at

low risk for the same disease (with certain exceptions such as cousin marriages

or diseases with high

prevalence in specific ethnic groups).

Cost

The new DNA-based tests are not especially expensive relative to other

diagnostic tests such as computed tomography (CT), magnetic resonance imaging

(MRI), and electromyogram (EMG). The DNA tests typically cost $250 to $800.

Also, the DNA tests are, in general, far more specific than other tests. In

fact, DNA mutations are often becoming part of the diagnostic criteria of

certain diseases. This is evident in the hereditary neuropathies where

individuals with highly similar Charcot-Marie-Tooth syndromes (CMT) may have CMT

1A (defined as a 17p 11.2 duplication), hereditary neuropathy with pressure

palsies (HNPP) (17p 11.2 deletion), CMT 1B (myelin P0 mutation) or CMT X

(connexin 32 mutation).[7] The potential " overuse " of any diagnostic test

(genetic, MRI or many others) is an important topic in medical economics and

must relate cost to benefit.

Negative Tests

Negative DNA tests are also important. They help clinicians continue the search

for other causes of the patient's symptoms. For example, if one patient is

initially thought to have myotonic dystrophy and another is thought to have HD,

but are subsequently found to have negative DNA tests for these disorders, then

the physician must continue the search for other explanations of each patient's

symptoms and signs. Two cautions must be noted with negative DNA results. First,

some DNA tests are so specific they may miss other genetic causes of the

syndrome. For example, the commercially available test for CMT 1A identifies

only the common 17p 11.2 duplication. A few patients will have CMT 1A on the

basis of point mutations in the PMP 22 gene, and these will not be identified by

that particular test.[7] Also, a patient with the CMT syndrome and a negative

test for CMT 1A may still have a genetic cause of neuropathy such as CMT 1B, CMT

X, or any of a number of

other inherited neuropathies. Thus, a negative genetic test does not exclude

all genetic possibilities. Second, there may be instances in which a patient

carrying a disease mutation may have symptoms mimicking the disease, but caused

by something other than the mutation. For example, a patient with a movement

disorder discovered to carry the mutation for HD might still have the movement

disorder actually caused by neuroleptic medication. Likewise, a patient with

ataxia found to have an abnormal spinocerebellar ataxia (SCA) gene mutation

might have the ataxia as a result of chronic alcoholism. Such situations

challenge the neurologist's diagnostic acumen and sometimes cannot be easily

resolved.

Unexpected Benefits

DNA testing may occasionally help patients obtain benefits they might have

otherwise missed. Our clinic has evaluated several persons at risk for HD who

were having serious difficulties at work and about to lose their jobs for

" incompetence. " The job difficulties were often related to problems with

attention, memory, or behavior. Early, subtle, signs of chorea were sometimes

noticed on neurological exam, but not evident enough for a definitive diagnosis.

DNA test confirmation of the HD mutation allowed these individuals to be

reassigned to less stressful jobs or to receive medical retirement with

pertinent benefits.

Treatment

In the future it is hoped that DNA testing will identify persons early in the

disease process who would be ideal candidates for treatment or prevention

measures. Such treatment or prevention is not presently available for most

neurogenetic disorders. Currently this strategy is of best use in genetic causes

of cancer where surgical treatments are available. However, even now, correct

identification of persons with the myotonic dystrophy or Freidreich's ataxia

genes allows for follow-up screening and treatment of the associated diabetes

and cardiac problems.

Testing Asymptomatic At-Risk Patients

The other major scenario in DNA testing is the genetic evaluation of

asymptomatic individuals who are at risk for inheriting a disease mutation. This

is also referred to as predictive or presymptomatic testing. In many ways this

is a new phenomenon in the practice of medicine. Such DNA testing allows us to

identify with great accuracy individuals who are highly likely to develop

serious untreatable degenerative disorders decades prior to the onset of any

symptoms. There are enormous potential risks and benefits associated with such

testing. Many of these risks and benefits are complex and many may not be

obvious to either the physician or the patient. The long-term consequences may

be serious and there can be no retreat once the test results are known. For

these reasons it is considered wisest for most DNA testing of asymptomatic

individuals to be performed in the context of professional genetic counseling in

genetic centers with experienced physicians

and board-certified genetic counselors. Most specialists as well as general

physicians lack the time and expertise to provide detailed genetic counseling.

Such counseling may sometimes seem to be time consuming and an unnecessary

expense, or even occasionally considered an unneeded intrusion by physicians or

patients. Although there may be exceptions to the general rule of genetic

counseling in this context, it usually proves to be time well spent. The most

widely studied condition for which asymptomatic DNA testing has been available

is HD.[8] HD has several characteristics that make it different from many other

neurogenetic diseases such as being associated with a prominent movement

disorder, cognitive and behavioral problems, and a decreased life span.

Nevertheless, DNA testing of asymptomatic persons at risk for HD is presently

the best available model of this practice.[9] Much of the recent genetic testing

literature refers to autosomal dominant

diseases, such as HD, where persons with a positive test have a high

probability of developing the disease in a normal life span. This is to be

distinguished from autosomal recessive diseases in which carriers of a single

copy of the disease gene will not develop any clinical symptoms.

Stress And Anxiety

Probably the most common reason given by patients for requesting predictive DNA

testing is to relieve stress and anxiety. Such patients often relate unremitting

daily mental and emotional stress associated with being at 50% risk for

inheriting a severe autosomal dominant neurological disease. Many recognize

that, especially at young adult ages, the risk of having the disease gene is

essentially the same as not having it. However, the lack of symptoms often make

such persons feel " normal " and often raises their hopes that the odds are

heavily in favor of not having the disease mutation. This is particularly true

of older persons who believe that they have " escaped " the disease risk because

of advanced age. It must be emphasized to all persons that they definitely

remain at risk, even though the risk may be lower with advancing age. We have

seen more than one elderly individual (over the age of 70 years) at risk for HD

who assumed that they could not have

the HD mutation, only to discover that they had indeed inherited it and their

children were at risk.[10]

Some persons clearly recognize that they have a 50% risk for inheriting a

disease mutation, but they truly feel that " knowing for certain " (one way or the

other) is preferable to many years of agonizing over the unknown. We have

certainly seen persons who have maintained this attitude even after testing

positive for severe disorders such as HD or SCA [3].

Long-Range Planning

Asymptomatic persons at risk may also want to learn their genetic status to aid

in making important long-term plans. Such issues may include whether or not to

have children, how many children to have, selecting adoption over biological

children, or making career and financial plans.

Depression/Support

Depression is a serious risk for persons who have tested positive for a

neurogenetic disease. The potential for suicide is a special concern.[11] For

these reasons, patients requesting DNA testing should be carefully questioned

regarding their potential for depression. If the potential is high (for example

in persons with a past history of depression), the genetic counseling should be

done in parallel with appropriate psychiatric or psychological counseling. The

psychologist or psychiatrist should be aware of the patient's past history, the

reasons for genetic testing, the possible outcomes of testing, and the natural

history of the pertinent neurogenetic disease. Fortunately, thus far, there have

been relatively few serious depressive outcomes discovered with the HD testing

model.[12-14] However, there are no long-term results because such testing has

only been available for a few years. Furthermore, it is instructive that only a

minority of individuals

(less than 25%) at risk for HD have elected to undergo DNA testing.

It is strongly recommended that patients be accompanied through the testing

process with an individually selected support person.[15] This is most commonly

a spouse or a close friend. It is preferable for the support person not to be

another family member who is also at risk for the disease. It is also preferable

for siblings at risk not to be tested simultaneously in the same clinic. (These

guidelines need to be somewhat flexible and we have made occasional exceptions.)

Patients should also determine prospectively with whom they plan to share test

results. Some persons keep these results private, and others disclose them to a

large circle of family members and friends. Whether or not to inform co-workers

or an employer is especially important. In general, DNA test results are highly

private and rarely shared with many other persons.

Insurance/Employment

The sharing of test results is especially pertinent in the context of insurance.

Legitimate concerns have been raised about the potential availability or

unavailability of both health and life insurance to persons undergoing DNA

testing.[16-17] Insurance companies often point out that if they pay for the

test they have a right to the result and that insurance premiums have

traditionally been scaled according to other health risks such as smoking,

alcohol, and hypertension. On the other hand, there is a fear that DNA testing

will produce a group of genetic social outcasts: persons known to carry a

disease gene who are unable to obtain certain benefits such as insurance or

employment. It is important and sobering to recognize that we all carry

disease-risk mutations, but we are presently only able to identify a small

number. These issues of insurance/employment and genetic testing are being

actively addressed by state and federal legislatures.

What DNA Testing Does Not Predict

It is important to carefully distinguish between finding a mutation in a disease

gene and determining that an individual " has the disease. " A positive DNA test

simply indicates that an abnormality has been found in the DNA sequence of a

gene associated with a specific disease. The person " carries " the disease

mutation. However, actually having a disease implies demonstrating clinical

symptoms and signs of that disease. Therefore, having the mutation is not the

same as having the disease. A physician must still judge whether symptoms and

signs of the actual disease are present. Furthermore, most positive DNA tests

are completely unable to predict the age of onset, severity, or exact types of

symptoms that will occur in the person with the mutation. Persons who know they

carry a disease gene often have a heightened awareness of possible symptoms, and

may misinterpret everyday occurrences (such as forgetting a name, dropping a

glass, or stumbling on the

stairs) as the first sign of disease manifestation. Patients need to be

cautioned not to overinterpret these common occurrences.

The results of some DNA tests do have a relative correlation with age of onset

or severity of symptoms. This is true of the disorders associated with

trinucleotide repeat expansions.[18] Longer expansions statistically correlate

with younger onset and increased severity of disease symptoms. However, except

at the extremes of expansion number, this correlation is not useful in

counseling individual patients.

Some diseases associated with trinucleotide repeat expansions, such as HD and

myotonic dystrophy, may have expansion numbers that are " equivocal " or

" intermediate. " [10,18] The repeat number may be associated with reduced

penetrance during a normal life span or may fall into a repeat range, where

disease symptoms are not expected in the proband, but children are at increased

risk for the disease. Such a finding may make it difficult to arrive at a clear

genetic diagnosis and create further stress and frustration for the patient.

There are also many diseases in which penetrance is reduced. This means some

persons having a disease mutation will die of other causes and never manifest

signs of the disease. This is especially true of persons who die at relatively

young ages. For example, some individuals with the HD gene may show no signs of

the disease even in their 60s and only 30-40% of persons having the dominant

torsion dystonia gene will ever show clinical manifestations of the disorder.

Therefore, information about penetrance should be included in discussions with

patients prior to DNA testing.

Testing Children

DNA testing of children is also an important issue. The general principle of

genetics clinics is not to do DNA testing of asymptomatic children.[19] There

are several reasons for this approach. One is the concern that children testing

positive will be treated differently by their parents, friends, and teachers. It

is naïve to expect that test results would be kept secret from all acquaintances

over many years. The so-called self-fulfilling prophecy is a legitimate concern,

referring to the fact that any and all problems experienced by the child would

be considered " caused " by the disease gene carried by the child. Also, it makes

more sense for an individual to be able to choose or not choose genetic testing

for his or her own self when he/she becomes a legal adult (18 years in this

country). One exception to the rule of not testing children is in the situation

where the child may be symptomatic for the genetic disease. In this case the DNA

test becomes

part of the differential diagnostic testing of a symptomatic individual and the

accurate diagnosis may have important treatment or care implications. The

testing might also save an expensive and exhaustive battery of other less

specific tests. This exception should be followed carefully and applied only to

children who are having symptoms highly likely to be related to the genetic

disease rather than vague and common symptoms.

It should also be noted that in many states a pregnant girl is considered an

adult even if she is below the age of 18.

Adoption

Another variation on the theme of testing children is the role of DNA testing in

adoption. Should children at risk for neurogenetic disorders have DNA testing

prior to being put up for adoption? Does the adoption agency or the potential

adoptive parents have a right to such information? The general principle stated

above should continue to be followed, that is, genetic testing of asymptomatic

children should be avoided. A corollary question is whether potential adoptive

parents should be at least informed of a child's risk for a genetic disease.

This question should be answered on an individual basis according to local law.

Prenatal Testing

DNA genetic testing can also be done prenatally on a fetus at risk. The diseases

under discussion here do not have effective treatments. Thus, prenatal diagnosis

in this situation involves a decision by the parents to carry a fetus without

the mutation to term, but to perform an abortion on a fetus found to have the

disease mutation. This raises all the complex spiritual, ethical, and legal

issues surrounding abortion. In general, DNA testing for prenatal diagnosis of

autosomal dominant neurogenetic disorders is quite uncommon, but has been

reported for HD.[12] It is obviously important to avoid the situation in which a

fetus has tested positive for a disease mutation and the parents then change

their mind and carry the pregnancy to term. This is the equivalent of testing an

asymptomatic child. Also, in most instances of prenatal diagnosis one of the

parents is known to carry the disease gene. However, in certain situations it is

possible to do exclusion

testing (by genetic linkage analysis) in which the presence of the mutation can

be excluded in the fetus without identifying the mutation status of the parent

at risk. In such a case if the mutation cannot be excluded in the fetus, the

parent remains at 50% risk and the unborn child remains at 25% risk.

25% Risk

Some individuals requesting DNA testing are at 25% risk for the disease gene.

These are persons who have an affected grandparent with an autosomal dominant

disease. Therefore the individual's parent is at 50% risk and the individual has

half the parental risk (25%). The problem with this situation is that if the

person at 25% risk is discovered to have the disease mutation, then you have

also determined that their parent must carry the disease mutation. Thus, two

persons are actually being tested. A conflict arises if the parent does not wish

testing, does not want to know his/her genetic status, or is unavailable to

determine his/her attitude and desire towards testing. The best approach in this

situation is to encourage all parties to discuss the various alternatives and to

come to a mutual agreement regarding testing strategy. This may take

considerable time and diplomacy, but an agreement can usually be reached. In any

event, the usual long-term

guideline is to proceed with testing the person at 25% risk if they are clear

in their desires and have made a legitimate attempt to reconcile family

disagreements.

Coercion/Third Parties

When DNA genetic testing is requested it is always important to question " Who is

asking for this test and why are they asking? " Potential coercion or strong

interests of a third party should be carefully considered. We have experienced

requests for genetic testing of individuals at risk for HD in the following

situations:

The person at risk is charged with homicide and the defense attorney has

requested the test.

The person at risk is in prison and requests the tests after a discussion with

the prison doctor.

A person at risk is entering a court proceeding to determine custody of his two

young children.

A school district requests testing of an elementary teacher at risk.

A corporation physician requests testing of an at-risk person employed as a

fireman at a large plant.

A military physician requests testing of an at-risk active duty soldier.

In these and similar situations one needs to carefully sort out all the reasons

for the requested test and the potential implications. The results may or may

not be in the best interests of the patient and the testing should only be

performed with the consent of the patient and his/her understanding of the

likely social and legal results of a positive test.

Legal Counsel

In some instances it may be helpful or indeed wise to seek legal counsel

regarding some of the complex issues surrounding DNA testing. It is clearly

important to attempt to anticipate and avoid legal problems before they occur.

Knowledgeable attorneys will be able to interpret existing pertinent law and

advise the best legal course of action. One must often proceed with caution, use

best medical judgment, and recognize that the law in this area may be ambiguous

and changing.

Test Availability

A final difficulty is that the discovery of disease genes is far ahead of the

availability of genetic testing. Physicians and families often learn of new

disease gene discoveries only to find that DNA testing for persons at risk is

not available and may not become available in the foreseeable future. This lack

of availability is partly caused by the understandable and necessary delay in

assuring quality control and accuracy of any commercially available laboratory

test. The delay may also be caused by the technical difficulty of a DNA-based

test that sometimes requires extensive, complex, and expensive sequencing of

large genes. The delay is sometimes also the result of a lack of interest by

commercial laboratories in pursuing tests for rare diseases for which there will

be little demand. The relative rarity of the disease, for example, explains why

DNA testing is not available for mutations in the amyloid precursor protein or

presenilin 2 genes that

sometimes cause early onset familial Alzheimer's disease or in genes

responsible for several types of limb-girdle muscular dystrophy.[20,21] In such

situations, some research laboratories will continue to test individuals in

specific families ascertained in their research studies in an experimental

context approved by institutional human subjects review boards. Many research

laboratories, however, have no interest in pursuing clinical DNA diagnostic

testing because their research focus and resources lie elsewhere.

A useful up-to-date listing of tests available for genetic disorders can be

found through Genetests, an on-line genetic testing resource: www.genetests.org.

Conclusion

The purpose of this discussion has been to emphasize the complex nature of DNA

testing for neurogenetic disorders. On one hand, such testing is highly

sensitive and specific and is extremely valuable in differential diagnosis. On

the other hand, the testing of asymptomatic persons at risk for a genetic

disease has genuine potential benefits, but is also fraught with serious and

sometimes unforeseen risks. It is clearly prudent for the physician and patient

to carefully address these potential risks and benefits prior to any testing and

to base the decision to test or not to test on the best available knowledge

appropriate to each individual circumstance.