Genetic testing for Huntington’s Disease

GENETIC TESTING PROTOCOL FOR

HUNTINGTON’S DISEASE

You can obtain a copy of the “Genetic Testing Protocol for Huntington’s Disease”

by emailing HDSA at [email protected]

FOREWORD

Since the advent of genetic testing for Huntington’s disease, the Huntington’s Disease Society

of America (HDSA) has played a key role in establishing guidelines for safe and effective testing.

As recent advances in both basic and clinical research lead to the promise of new opportunities

for treatment and care, HDSA has revisited these guidelines to ensure that they continue to

reflect best practices for both diagnostic and predictive testing.

This document was written by HDSA with input from clinicians, laboratory professionals, and

individuals at risk for HD to provide guidance for genetic testing for Huntington’s disease (HD).

In 1983, Huntington’s disease became the first disease to be mapped to a previously unknown

genetic location on chromosome 4. Over the past 30 years, genetic testing for Huntington’s

disease has progressed from the identification of linked genetic markers to the development of

direct genetic testing. Throughout that history, groups such as the Huntington’s Disease

Society of America, the International Huntington’s Association, and the World Federation of

Neurology have provided recommendations for testing to health professionals wishing to

provide such testing, as well as to individuals affected and at risk for HD who wish to pursue

testing.

While technological advances have made genetic testing for HD faster, cheaper, and more

accurate, predictive testing for HD remains a process with the potential to have profound

implications for the life of an individual who chooses to be tested. So while we favor

eliminating barriers to testing to the extent possible and maintaining flexibility in the way that

testing is offered, experience has shown that the following elements are essential to the testing

process: pretest counseling, informed consent and in-person results. A child should not be

tested unless the child is exhibiting symptoms that cannot be attributed to any other condition.

HDSA hopes that this publication will be useful to those working with people with Huntington’s

disease and their families, as well as the families themselves.

TABLE OF CONTENTS

PREFACE …………………………………………………………………………………………. 4

SECTION 1 ……………………………………………………………………………………… 5

Introduction

Historical Background

Direct Gene Test

Clinical Uses of the Gene Test

SECTION 2 …………………………………………………………………………………….. 8

Predictive Testing

SECTION 3 ……………………………………………………………………………………… 13

Confirmatory Testing

SECTION 4 ……………………………………………………………………………………… 14

Prenatal Testing

SECTION 5 ……………………………………………………………………………………… 16

Testing of Minors

Anonymous Testing

Testing Two People with One Test

Results of Intermediate Alleles

SECTION 6 ……………………………………………………………………………………… 18

Conclusions

SECTION 7………………………………………………………………………………………. 19

References

SECTION 8………………………………………………………………………………………. 20

Acknowledgements

PREFACE

This protocol has been produced by the Huntington’s Disease Society of America to assist

genetic counselors and other healthcare professionals involved in the genetic testing process

for Huntington‘s disease and to protect the well-being of individuals who choose to be tested.

The protocol is a framework of recommended procedures for testing; they are not regulations.

Each provider, center, or institution that offers genetic testing for HD and each testing situation

is unique. Providers must ensure that testing is performed safely despite variations among

patients, personnel, and geography. The Huntington’s Disease Society of America is particularly

concerned about genetic predictive testing -- testing in asymptomatic individuals. HDSA

maintains a list of centers where predictive testing protocols appear to meet the best practices

described within. For more information on this list, please contact HDSA at [email protected].

HDSA first published “Guidelines for Predictive Testing for Huntington’s Disease” in 1989. A

revision entitled “Genetic Testing for Huntington’s Disease” was published in 1994 and revised

in 2003. The current document reflects over two decades of experience with genetic testing for

HD and is based on a review of the previous HDSA guidelines, the experiences of many who

have been tested or who offer the tests, and the growing body of knowledge about genetic

testing for many other diseases.

SECTION 1

INTRODUCTION

Huntington’s disease (HD) is a hereditary neurodegenerative disorder. The HD gene is present

from the time of conception and is inherited in an autosomal dominant fashion, meaning that

each child of an affected parent, regardless of gender, has a 50% chance of inheriting the

disease-causing gene. The prevalence of HD is estimated at 1/10,000 individuals in the United

States; thus, the population to whom genetic testing might be applied includes approximately

30,000 affected individuals and 200,000 at-risk individuals.

The typical onset of HD symptoms is between ages 30-50. However, onset of symptoms has

been seen in children under 5 years of age or as old as 90 years. There is an inverse

relationship between the size of the pathogenic variant (CAG repeat expansion) and the age of

symptom onset, in general, larger gene expansions are associated with earlier onset ages,

although other factors may also influence the age of onset. Occasionally, individuals with a

lower CAG repeat expansion may live up to or beyond a normal lifespan without developing

symptoms. However, except for these unusual cases, the presence of an HD gene with a CAG

repeat expansion is always associated with the development of HD symptoms

The early symptoms of HD vary and may be subtle enough to go undetected. These symptoms

may include behavioral changes such as depression and mood swings, minor twitching,

fidgeting, clumsiness, changes in gait, and lapses in judgment and memory. Symptom

progression is likewise extremely variable. As the disease progresses, involuntary movements,

particularly chorea, may become more pronounced. Speech and swallowing difficulties often

develop and cognitive ability deteriorates. In the later stages of the disease, the affected

individual is usually bedridden and totally dependent on others for all of his or her needs. The

duration of symptoms may range from 10 to 25 years or more. Death is typically due to

complications such as malnutrition or aspiration pneumonia.

For more information on Huntington’s disease, including resources for professionals and family

members, please visit www.hdsa.org or contact the HDSA National Helpline at (800) 345-4372

or by e-mail at hd[email protected].

HISTORICAL BACKGROUND; CAG REPEAT EXPANSION

In 1983, in one of the early triumphs of the molecular genetic era, researchers at

Massachusetts General Hospital located the marker for the gene that causes Huntington’s

disease (Gusella et al, 1983). This discovery paved the way for the development of a

presymptomatic test for HD using a technique called linkage analysis, which was first offered to

individuals at risk for HD on a research basis in 1986.

Because this test relied on tracing the inheritance of genetic markers linked to the huntingtin

gene rather than the gene itself, analysis of DNA samples from multiple affected and unaffected

family members was necessary and the test was only 95% accurate. As more markers closer to

the HD gene were identified, the test became more accurate. By the late 1980s, over 20

centers around the country offered the genetic linkage test as a clinical service.

Ten years after the first marker was found, the HD gene itself was finally identified

(Huntington’s Disease Collaborative Research Group, 1993). The gene is known as the IT-15

gene, which encodes the huntingtin protein. The abnormal HD gene contains an expanded and

unstable DNA segment, which is composed of the trinucleotide cytosine-adenine-guanine (CAG)

repeated a number of times in a row. The repeating CAG fragment is longer on the expanded

gene than on the normal huntingtin gene and is unstable, sometimes changing in length when it

is passed to offspring. Worldwide experience suggests the following interpretations for the

results of HD genetic testing (Nance, Paulsen, Rosenblatt, Wheelock, 2011):

CAG REPEAT SIZE INTERPRETATION

26 and below Normal

27-35 Normal, unstable (sometimes called the

“intermediate range”)

36-39 Abnormal; reduced penetrance, unstable

(sometimes called the “indeterminate range.”)

40 and above Abnormal/Huntington’s disease

To clarify this table further, any number of CAG repeats that is less than or equal to 26 is

considered normal. Within this range, the size of the CAG repeat segment also appears to be

stable; i.e., does not appear as prone to expansion. CAG repeat lengths within the range of 27-

35 are also normal and they are not associated with symptoms of HD. However, the CAG

repeat length tends to be more unstable in this range and can increase, so that a parent with a

repeat number in this range can have a child whose repeat number is in the HD range. If the

number of CAG repeats is within the range of 36-39, whether or when HD symptoms will

develop cannot be predicted with certainty. Within this range, some individuals have been

found to have classic symptoms of HD, while others have lived to be very old without

developing the symptoms of HD. The gene is unstable in this range and may expand, so that a

child may have a number of CAG repeats that is clearly within the HD range. CAG repeat

lengths of 40 or greater are virtually always associated with the development of the symptoms

of HD at some time during a normal life span.

Large increases in CAG repeat length are more likely to occur when the HD gene is passed on to

a child by an affected father (Hendricks et al., 2009). While CAG repeat length is a significant

factor in determining the age of onset of HD symptoms, it is not the only factor. The CAG

repeat length does not predict with any accuracy when a particular individual’s symptom onset

will be or the clinical course that the disease may take. Two individuals with similar CAG repeat

lengths may have different ages of onset and different symptomology.

A DIRECT GENE TEST FOR HD

Since the development of the direct test for the HD gene by analysis of CAG repeat length,

many centers have been established around the country to provide the genetic counseling and

psychological support services that allow predictive testing to be performed in a timely,

sensitive, and knowledgeable manner. Although HDSA maintains a list of centers that meet the

standards set forth in this protocol, HDSA does not certify, promote, or advertise any predictive

testing center, nor does it have any means to monitor or modify how testing is actually

performed at the centers or associated costs.

There is still no cure for HD and no treatment proven to delay the onset or slow the progression

of the disease. Certain medications and treatments are available that sometimes help alleviate

specific symptoms associated with HD. The emotional and ethical issues that accompany the

diagnosis of HD or the detection of the presence of the disease-causing gene in an

asymptomatic individual remain significant, potentially devastating, and unbalanced by medical

benefits or advances. The importance of genetic counseling and support of the individual

undergoing testing remains undiminished.

CLINICAL USES OF THE GENE TEST

The gene test is useful in three clinical situations: for predictive testing in an asymptomatic

individual known to be at risk for carrying the gene, for confirmation of a suspected diagnosis of

HD, and for prenatal diagnosis and preimplantation genetic diagnosis (PGD). Each of these

clinical situations will be reviewed separately, and certain special situations will be discussed at

the end.

Special consideration should be given to the cost and accessibility of genetic testing, since the

cost of testing is often a deterrent for individuals considering genetic testing. HDSA encourages

clinics to consider ways to make the testing process as inexpensive and accessible for the

individual as possible.

SECTION 2

PREDICTIVE TESTING

In this section, the term “Individual” refers to the person who seeks a predictive genetic test, to

distinguish him or her from the “patient” who seeks medical attention because of symptoms.

Below, after a discussion of general principles important for predictive testing, is a list of the

specific recommended components of the testing process.

In the United States, predictive testing is requested by a relatively small proportion of people at

risk for HD. The reasons commonly given by those undergoing predictive testing include future

planning regarding marriage, reproduction, career, finances, or simply a need to relieve

uncertainty. Because there are currently no direct medical benefits from predictive testing, it is

incumbent upon the health professional to help the Individual who requests the test to balance

the potential psychological or social risks of testing against the benefits he or she believes it

may provide. These potential risks may include changes in the Individual’s perception of self,

stresses in relationships with friends or family, discrimination in the workplace or community,

difficulties obtaining/retaining insurance such as disability, life, and long term care insurance,

and other concerns related to privacy and confidentiality. In many testing centers, a team of

designated members, the HD predictive testing team, has been assembled to provide the range

of services and counseling that are appropriate for an Individual considering predictive testing.

The decision to take a predictive test for HD must always be an informed, carefully considered,

and freely-chosen personal decision. An Individual must not be pressured into testing by a

spouse, another family member, a health care provider, an insurance company, or an employer.

Timing

Predictive testing should ideally take place in a supportive environment during a time period

when the Individual is not otherwise stressed. Testing must not be accompanied by a sense of

urgency or emergency and should be considered in a cautious manner. It is important to

include enough time in the counseling process so that the Individual can fully consider the

implications of the test and have a chance to reconsider his or her decision.

Confidentiality

Confidentiality is of utmost concern to Individuals undergoing predictive testing, for whom the

untimely release of private genetic information could have serious adverse effects on personal

and professional relationships, community standing due to prejudices, or self-esteem. Testing

centers must ensure that all appropriate measures are taken to preserve the privacy of genetic

testing information and results without compromising the person’s medical safety.

Test results must not be divulged to anyone other than the Individual without his or her written

consent. If test results are used for research purposes, all identifiers must be removed unless

the Individual specifically permits otherwise. Only in exceptional circumstances, such as

prolonged coma or death, may information about an Individual’s gene test result be released to

the next of kin.

Any communication between the testing team and family members must be discussed in

advance with the Individual. For example, if a blood sample from another family member is

needed to confirm a genetic diagnosis of HD, the Individual should speak with the relevant

family member first. The testing team must ask for guidance from the Individual about

communications from the team, such as leaving voice mail messages, mailing HD materials to

the home or workplace, or emailing.

Support System

The Individual is encouraged to identify a companion (such as a spouse or close friend) to

accompany him or her through the testing process. The companion, by being physically present

during counseling sessions, can gain insight into the Individual’s testing experience and thus

become a uniquely valuable source of support. The Individual is discouraged from bringing

another at-risk person or someone who may have a negative or difficult reaction to the

Individual receiving a positive diagnosis of Huntington’s disease. An Individual who cannot or

does not want to identify a testing companion cannot be excluded from testing.

Identification of a local counselor is also recommended, particularly if the Individual lives some

distance from the testing site. The counselor may be a psychologist, social worker, school

counselor, minister, or other professional. The counselor should be available for emotional

support or counseling as needed. The predictive testing team must have permission from the

Individual to communicate with the local counselor as needed to provide information about HD

and predictive testing.

Active psychiatric problems must be stabilized before an Individual undergoes predictive

testing. Predictive testing cannot proceed if the responsible health professional believes it

would be harmful to the Individual.

Neurological Evaluation

Neurological evaluation may be offered prior to the predictive test to any Individual who is or

might be concerned about possible symptoms. A normal neurological exam can sometimes be

sufficiently reassuring that predictive testing is no longer desired. However, refusal of a

neurological examination cannot exclude the Individual from predictive testing.

Recommended Components of Predictive Testing

The recommended components of predictive testing are shown in Table 1 and described

starting on page 11. Many predictive testing centers have been established around the country

where teams of experienced clinicians provide these services. Physicians are strongly advised

to refer appropriate Individuals for testing to a designated HD predictive testing center.

Items listed in Table 1 are part of the recommended predictive testing process, but the order in

which they occur is not rigid and may be varied as appropriate for a particular testing Individual

or center.

Recommended Components of

HD Predictive Testing Process:

1. Telephone Contact

2. Visit 1

- Genetic Counseling

- Sign Informed Consent Document

- Mental Health Assessment

- Neurological Exam

- Draw Blood

3. Visit 2

- Disclosure of Results in Person

- Arrange Post-result Follow-up

4. Follow-Up

- Prearranged phone call or in-

person visit

HDSA recommends two in-person visits for an Individual requesting predictive genetic testing

unless concerns on the part of the testing team arise during the initial call or first in-person

appointment that would necessitate additional services.

Additional services beyond those listed may include (but not be limited to) neuropsychological

testing, personality inventory, additional visits with the genetic counselor or mental health

professional, establishment of contact with a counselor outside of the testing program, and

scheduled post-test follow-up sessions. Additional support or counseling for the Individual’s

primary support person or family may sometimes be necessary.

Table 1.

1. Telephone Contact

The purpose of this call is to help the

Individual at risk understand the genetic

testing process. During the initial telephone

contact, which must be by the Individual,

information about the testing process,

costs, and risks is provided by a healthcare

professional experienced in genetic

counseling and testing for HD. Concerns

about symptoms and whether the

Individual may wish to include a

neurological exam as part of the predictive

testing process are also discussed.

Insurance: An Individual will be advised to consider whether he or she wishes to obtain life

insurance, disability insurance, and/or long term care insurance prior to testing, since these

types of insurance are not protected by federal law. The healthcare professional will also

discuss whether the Individual wishes to utilize his or her health insurance to pay for testing or

pay out of pocket for these costs.

Other information gathered: Demographic and medical history information about the Individual

is obtained. Pre-test tasks such as identifying a local counselor, confirming the diagnosis of HD

in a family member, evaluating neurological or psychiatric symptoms, or obtaining any of the

insurances described above are discussed and scheduled or performed if necessary. If the

Individual requires more time to prepare for the testing process, telephone conversations may

extend past one session.

Next steps: Subsequent to the call, the testing center sends a fact sheet or similar document to

the Individual that outlines the testing process at its facility including costs (See sample

information sheet provided by HDSA Center of Excellence at University of California, Davis Medical

Center https://www.ucdmc.ucdavis.edu/huntingtons/genetics.html).

2. Components of Visit 1:

After the in-depth telephone conversation, the Individual comes in for the first visit to meet

with the genetic counselor and receive a mental health assessment and a neurological

examination if the Individual agrees to one, and, if the clinic feels comfortable about the

Individual’s safety, a blood draw is performed.

 Genetic Counseling -- in person

This includes a review of the family history, confirmation of the family diagnosis, and

explanation of the Individual’s risk status. The genetic counselor will review genetic

principles that relate to HD and the gene test, including the risks, benefits, and limitations of

the test (such as the possibility of results in the intermediate range and the inability to

predict the age of onset based on repeat number alone). The genetic counselor will also

explore the Individual’s experience with HD and perceptions of the disease and discuss the

potential burden of the test results, positive or negative, on the Individual and the family.

 Documentation of informed consent

A signed document signifies that the Individual freely consents to this procedure. A copy of

the consent document may be sent with the blood sample to the testing laboratory to

ensure that only Individuals who have received counseling are tested.

 The Neurological Exam: An exam may be part of the predictive testing process at certain

testing centers but an Individual has the right to decline the exam if he or she so desires.

 Mental Health Assessment

The mental health professional assesses the Individual’s current emotional state so that

ongoing psychological problems, significant life stressors, or need for emotional support

beyond what is available as part of the testing program can be identified and managed

appropriately. It is important that the Individual not view a pretest mental health

assessment as an obstacle to testing. Rather, he or she should understand that such tests

might help counselors to identify those who may need greater emotional support during

and after testing. The mental health professional reviews the Individual’s support system so

that a plan for accessing help within the home or community is clear before results are

given. Specific ways to access emergency psychiatric services are provided. If the Individual

is already seeing a mental health professional, some clinics will coordinate with that

professional. The mental health assessment should be performed by a mental health

professional who has training in suicide assessment, such as a social worker, nurse,

physician, psychologist, or psychiatrist.

Adverse emotional responses constitute the major medical complication of predictive

testing. In some instances, such as overt risk for suicide and/or major depressive

symptoms, it is important for the mental health professional to initiate psychiatric

treatment and stabilize the Individual before making the decision on whether to proceed

with the test.

 Review of the Potential Impact of the Test

Many Individuals enter the predictive testing process after much thought about whether to

be tested. It is incumbent on the testing center to review the potential impact of the test

results with the Individual, both positive and negative, and to discuss the risks and possible

broader impact of the test. The genetic counsellor must discuss not only the emotional

impact of a “positive” result, but also implications of a “negative” result. Survivor’s guilt and

feelings of “having to make up for affected members of the family” should be part of the

comprehensive discussion of testing.

For some people, knowing whether they have HD can be very helpful for family planning

decisions. Financial planning concerns are another reason people may benefit from testing.

If an Individual is concerned that he or she is beginning to show symptoms of HD, he or she

may find relief in learning whether HD is present. While the exact effects of the gene test

cannot be known in advance, an informed decision to be tested requires that the Individual

be aware of and prepared to face these uncertain and potentially negative consequences.

Possible negative consequences include loss of self-esteem, as well as intense or painful

emotional responses. The test can change the Individual’s relationships with siblings,

parents, and his or her own spouse or children, sometimes in an unpredictable or negative

fashion. Relationships with friends and acquaintances may be altered. Finally, the test

results can also have deleterious effects on the Individual’s employability and insurability.

Some centers also make provisions for counseling the applicant’s companion or other family

members whose lives are affected by the results of the test.

3. Components of Visit 2:

 Disclosure of Results in Person

The genetic counsellor gives the results to the Individual in person to avoid any possible

miscommunication about this life-altering information. A supportive friend or family

member who is not at risk should accompany the Individual to the results visit. In-person

communication also begins the process of post-test supportive counseling and allows

specific arrangements for follow-up as needed. The Individual has the right to postpone or

cancel result disclosure.

 A subsequent phone call or an in-person visit should be arranged prior to the end of the

disclosure visit and should be based upon the Individual’s need for additional support.

4. Follow-up after Testing

Follow-up should be individualized to respond to the needs of the Individual. Ideally, the

testing center should initiate contact within a few weeks of test results to assess the

Individual’s adjustment to his or her results. Gene positive individuals should be provided

with information about clinical trials that are available. A baseline neurological

examination should be encouraged for gene-positive individuals who have not already

undergone one, and additional visits for supportive counseling should be offered as

needed.

SECTION 3

CONFIRMATORY AND DIAGNOSTIC TESTING

Confirmation of clinical diagnosis

Confirmatory testing by analysis of the HD gene is offered at or after the time of the clinical

diagnosis of HD. The presence of a CAG repeat expansion in a person with HD symptoms

confirms the clinical impression and supports a diagnosis of HD. The absence of a CAG repeat

expansion in a person felt clinically to have HD must prompt a re-evaluation of the person’s

diagnosis and a reconsideration of the accuracy of the diagnosis in the family. Molecular

confirmation of the diagnosis of HD in another affected family member might be indicated.

However, it is not essential for diagnostic reasons to perform a gene test in all people with

characteristic clinical features of HD and a molecularly confirmed diagnosis of HD in the family.

A person who comes in for predictive testing, but who shows symptoms that the clinician

suspects may be Huntington’s disease even though the person seeking testing does not notice,

should be treated as undergoing predictive testing since, for that person, it is a predictive test.

A positive HD gene test does not determine whether an individual’s symptoms are caused by

the gene. Only a clinical examination can determine whether a clinical diagnosis of HD is

warranted. The use of the HD gene test in a person whose symptoms are not typical of HD

(such as pain, fatigue, unilateral neurological signs, isolated depression, or non-neurological

symptoms) is strongly discouraged. A positive gene test could lead the physician or person to a

false supposition that the symptoms are due to HD and thereby prevent appropriate diagnostic

evaluation or treatment.

For some individuals and families, the confirmation of a clinical diagnosis of HD by a gene test is

a devastating event, since it establishes a diagnosis that was previously just a suspicion; for

others, it simply reiterates a recognized or expected diagnosis and adds no further

psychological burden. Counseling prior to the gene test and the availability of psychological

support after the test are important components of the diagnostic process. Those who are

confirmed to be gene positive should be referred to available HD clinical trials.

Some people may get a test result in the “intermediate” zone. This can lead to some confusion

for the Individual, since he or she will not be sure whether symptoms of Huntington’s disease

will ever develop or what risk his or her child might face. It is important for the counsellor to

discuss with these Individuals what it means to have a gene test within these boundaries.

Absent Family History

The family history of HD may be absent because of adoption, early death of a gene-carrying

parent, misdiagnosis of a family member, non-paternity, or a pathogenic variant from a parent

in the high normal allele range. The probability of a person in the high normal allele range

having an offspring with an expanded allele that may cause HD ranges from 1:6,241 to 1:951

(Hendricks et al., 2009). The diagnosis of HD may be unexpected in these cases, and provision

should be made for post-test support and counseling for family members who may request it,

as well as for the tested Individual.

Atypical Symptoms

Occasionally, an Individual may be strongly suspected of having HD despite atypical symptoms.

This might apply to Individuals with prominent psychiatric symptoms, atypical dementia

disorders, and unusual movement disorders, and to any child suspected of having HD.

Physicians must carefully consider the value and potential implications of establishing the

presence of the HD gene, recalling that the presence of the HD gene may not explain the

Individual’s symptoms. It may be appropriate in some circumstances to evaluate an Individual

with atypical symptoms several times over the course of a year to monitor whether the

condition is static, improving, or progressing in a manner consistent with HD, prior to obtaining

a gene test. This is particularly important for children, in whom the presence of symptomatic

HD is rare and different from adult symptoms, and for whom the premature detection of the

HD gene may have a greater negative psychological and social impact.

SECTION 4

PRENATAL TESTING

Individuals or couples considering prenatal testing are advised to seek genetic counseling prior

to a pregnancy. Many reproductive options are available to Individuals affected by or at risk for

HD, of which prenatal testing is one. Samples for prenatal analysis of the HD gene may be

obtained in two ways: by chorionic villus sampling at 10-12 weeks of pregnancy, or by

amniocentesis at 14-20 weeks. Some couples may also desire preimplantation testing of a

fertilized embryo. This requires the use of fertility drugs and other procedures available only at

specialized in vitro fertilization centers.

Direct Gene Testing

Chorionic Villus Sampling (CVS) is offered at some clinics for women from their 10

through

weeks of pregnancy. Amniocentesis can be done from the 14

through 20

weeks of

pregnancy. This process includes genetic counseling to explore the parents’ questions and

concerns and to educate them about the risks involved. It is important for parents to explore

what they hope to gain from this procedure, especially if they are not planning to terminate the

pregnancy. As with testing of asymptomatic minors, CVS and Amniocentesis take away the

child’s option not to know his or her gene status.

CVS and Amniocentesis can be done if a parent is at risk or if he or she has tested positive for

the gene that causes HD. If a parent has decided not to test, then genetic counseling must

include the impact for both the parents and child of getting a positive result for the fetus.

Testing the fetus when a parent does not want to know his/her own gene status can lead to a

difficult situation wherein the at-risk parent will come to know his or her genetic status as a

result of the fetal test. These instances require careful consideration.

Preimplantation testing

The development of the technology to perform Pre-implantation Genetic Diagnosis (PGD) offers

an option for couples seeking to have children who will be gene-negative and avoids issues

associated with terminating a pregnancy. PGD begins with the couple undergoing in vitro

fertilization (IVF). In IVF, eggs are collected from the mother by a transvaginal biopsy of the

ovaries and then fertilized in vitro (in a dish) by sperm collected from the father. The collection

of the eggs has to be carefully timed to the mother’s menstrual cycle and involves drug

treatment to enhance the ovulation process and careful monitoring by a fertility clinic prior to

the biopsy.

Because only a few eggs can be collected in the biopsy and are receptive to fertilization for a

brief time, fertilization is performed by injecting the sperm into the egg, which greatly increases

the likelihood of successful fertilization. The process is known as “intracytoplasmic sperm

injection” or ICSI.

The PGD test is performed on a single cell that is collected by a needle biopsy from the eight-

cell embryo (day 3 of development). The HD gene test is performed on the DNA from this

single cell allowing for the detection of the HD repeat sizes for that embryo. Only those

embryos testing gene-negative are implanted.

This procedure involves specific procedures and very specialized equipment for the various

biopsies, fertilization, and genetic tests. Those who perform these procedures are extensively

trained specialists, and therefore the procedure can be very expensive.

It is important for couples considering PGD to receive genetic counseling before beginning the

PGD process. There are several common questions that arise with PGD that should be discussed

with a genetic counselor.

Accuracy: The main concern for PGD is that the procedure involves the PCR

amplification of DNA from a single-cell, and there is the possibility for HD gene allele drop-out

to occur. This means that the HD gene allele from one of the two chromosomes does not

amplify and the test result is not precise. (Bui & Harper, 2002). Consequently, blood samples

are collected from both parents so that DNA can be studied simultaneously to ensure that both

a maternal and a paternal allele is detected. When both parental alleles are detected, the test

is very accurate and comparable to traditional HD testing from blood (>99% accuracy).

Success Rate: In vitro fertilization continues to have a fairly low rate of successful

pregnancy, with only 20% to 30% of couples achieving pregnancy per IVF cycle. (Mastenbroek

et al., 2007). According to the most recent report by the CDC (2009), the overall pregnancy rate

for IVF was 29.4% of all cycles (higher or lower depending on the age of the woman). The

percentage of cycles that resulted in live births was 22.4% on average (again depending upon

age of woman). Thus the success rate, even among experienced programs, does not lead to the

majority of couples achieving their goal of a live born child. There is a 25% risk of multiple births

using this method.

Risk for Birth Defects: IVF itself is not associated with an increase in the frequency of

birth defects. However, PGD utilizes intracytoplasmic sperm injection, which is associated with

an increased risk for birth defects. An increase of about 1.5 times as many birth defects is seen

with this procedure (Davies et al., 2012; Win J. et al., 2012).

Expense: Many insurance companies do not cover this cost for genetic testing even

when they may cover costs for infertility treatment. Since most women do not become

pregnant during the first IVF treatment, parents using this route may need to undergo multiple

IVF cycles in their efforts to have a child.

Non-disclosing test: Some programs offer PGD for couples who do not wish to undergo

HD presymptomatic testing (Stern et al., 2002). In this circumstance, parental gene status is not

revealed to the parent during the testing. This can lead to important ethical questions,

especially if it is discovered that the at-risk parent is gene negative (Erez et al, 2010).

SECTION 5

TESTING OF MINORS

Minors should not undergo genetic testing unless there is a medically compelling reason, such

as a clinical diagnosis or a strong suspicion of HD. In these unusual circumstances, testing must

be preceded by a complete neurological and neuropsychological evaluation. Parental anxiety

about a child’s risk does not constitute a medically compelling reason for genetic testing. A

positive gene test does not mean that a child’s symptoms are necessarily due to HD, and

premature confirmation of the presence of the HD gene in a child may distract the family or

physician from identifying other causes of the symptoms and lead to improper management.

Because of the vivid historical examples of the abuse of genetic information in nonconsenting

individuals, the principle of autonomy as embodied in the process of informed consent is held

with particular importance in genetics. The goal of the prohibition against testing minors is to

preserve the autonomy of the child to decide whether to be tested when the age of majority

(usually 18) is reached. Predictive testing of minors currently has no medical benefits and the

possibility for psychosocial harm and lowered self-esteem is high. The potential for

discrimination at the workplace, at school, or by insurance providers is also proportionally

greater in a younger individual. However, minors should not be discouraged from seeking

genetic counseling if they have questions about their at-risk status or future options.

The recommendation not to test minors includes situations in which prospective adoptive

parents wish to have a child who is at risk tested for the HD gene prior to adoption. If a

negative test, showing that the child does not carry a gene with an expanded CAG repeat

influences the prospective parents to proceed with adoption, a positive test might, conversely,

consign the child to permanent foster care.

Exceptions to the prohibition against testing children might be made in the case of

“emancipated” minors, such as those who are married or pregnant. Another consideration

might be an older child at risk who is aging out of foster care and has major life decisions to

make. Requests for testing by adolescents at risk may be considered on a case by case basis,

but the primary consideration should be that the child or adolescent is making the request by

and for himself or herself and not at the request of a third party, regardless of whether it is

parents, foster parents, school employees, employers, physicians, or members of the justice

system such as lawyers or judges.

ANONYMOUS TESTING

The advent of direct gene testing makes it possible for a person to be tested without the

involvement or knowledge of other family members. All testing centers adhere to basic

standards of medical confidentiality. However, some individuals have exceptional concerns

about confidentiality and desire “anonymous” testing. Although anonymous kits or procedures

are available for HIV testing and pregnancy testing, this approach has not yet been applied to

genetic tests. Because there is no standardized definition of anonymity nor an accepted means

to remove some or all identifiers from an Individual’s medical file or test requisition form, the

center and the Individual must discuss and agree on how best to meet the Individual’s needs or

desires. An Individual’s desire for anonymity may create a barrier to the supportive relationship

that the counselor seeks to establish and can make subsequent care for psychological or

neurological symptoms more difficult to provide. Some centers may decline to or may be

unable to perform predictive testing anonymously, but depending on the situation or Individual

seeking anonymous testing, other centers may be willing to work with the Individual to provide

the desired service. Whether a person tests negative or positive for HD through an anonymous

test, he or she may need to be retested at a later date for their medical file.

TESTING TWO PEOPLE WITH ONE TEST

Occasionally, an Individual may request predictive testing because his or her parent has a 50%

risk of having HD, though the parent is not yet affected, is unwilling to be tested, or is alienated

from the Individual. Performing this test is equivalent to testing two people, perhaps without

the knowledge of, or even against the will of, one of the two parties. This is a challenging

genetic counseling session in which shared decision making is crucial in determining whether

the applicant’s desire to know his or her gene status supersedes the parent’s right not to know.

A more in-depth discussion with the Individual is warranted in these cases to ensure he or she

understands what his or her gene positive result means for the parent and siblings. If the

whereabouts of the at-risk parent is known, every attempt should be made by the Individual to

discuss his or her desire to be tested with the at-risk parent. Some parents may be aware of

the Individual’s desire and agreeable to the decision to be tested, while others may not. Some

centers may refuse the request because of the potential harm to the non-consenting parent.

Other centers may consider such requests individually. Consultation with an institutional Ethics

Committee or legal counsel may be helpful to a center that is considering such a request.

The second situation in which it is possible to test two people at once is when the Individual is

an identical twin. If the twins truly are identical and not fraternal, testing one twin will reveal

information about the other twin. This, too, is an ethically difficult situation, and counselors

should explore, to the extent possible, the needs and desires of the other twin about testing as

well as social circumstances and family relationships. Consultation with an Ethics Committee or

legal counsel may be helpful.

RESULTS OF INTERMEDIATE ALLELES

Sometimes the person being tested receives a result in the intermediate or reduced penetrance

range (27-39). People with this genetic determination might or might not eventually exhibit

symptoms associated with HD. In this situation, a genetic counselor can help a person

understand what this means for both the person at risk and his or her offspring. A discussion of

this possibility should be mentioned during the initial genetic counseling session (Semaka et al.,

2011; Brocklebank et al., 2009).

SECTION 6

CONCLUSIONS

Genetic testing for HD is a straightforward procedure, but should not be considered a simple

blood test. An Individual who has a gene test should have access to an accurate and up-to-date

interpretation of the results and competent support for the complex psychological and social

consequences of the results. Although the medical value of predictive testing will change

dramatically if treatments to prevent or delay the disease are developed, the psychological and

social aspects will continue to be challenging, and the need for sensitive, timely, and accurate

counseling will remain.

SECTION 7

REFERENCES

Brocklebank D, Gayan J, Andresen JM, Roberts SA, Young AB, Snodgrass SR, Penney JB, Ramos-Arroyo

MA, Cha JJ, Rosas HD, Hersch SM, Feigin A, Cherny SS, Wexler NS, Housman DE, Cardon LR,

International-Venezuela Collaborative Research Group. Repeat instability in the 27–39 CAG range of the

HD gene in the Venezuelan kindreds: counseling implications. Am J of Med Genet B: Neuropsychiatr

Genet 2009 Apr 5; 150B (3), 425-9.

Bui TH, Harper JC, (2002) Pre-Implantation genetic diagnosis, Clinical Obstetrics and Gynaecology, 16(5):

659-70

CDC (2009) Assistive Reproductive Technology Success Rate, WebMD, January 18, 2015

Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, Haan EA, & Chan A. Reproductive

technologies and the risk of birth defects. N Engl J Medicine, 2012, May 10; 366(19), 1803-13.

Erez A, Plunkett K, Sutton VR, & McGuire AL (2010). The right to ignore genetic status of late onset

genetic disease in the genomic era; Prenatal testing for Huntington disease as a paradigm. American

Journal of Medical Genetics Part A, 152(7), 1774-1780.

Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE et al (1983) A polymorphic DNA

marker genetically linked to Huntington’s disease. Nature 306: 234-238

Hendricks E, Latourelle J, Lunetta K, Lupple A, Wheeler V, MacDonald M, Gusella J, Myers R (2009)

Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in

the Huntington disease gene from male carriers of high normal alleles (27–35 CAG) AJMG 149

The Huntington’s Disease Research Collaborative Group (1993) A novel gene containing a trinucleotide

repeat that is expanded and unstable on Huntington’s disease chromosomes, Cell 72: 971-983

Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, & Buys CH

(2007). In vitro fertilization with preimplantation genetic screening. New England Journal of Medicine,

357(1), 9-17.

Nance M, Paulsen J, Rosenblatt A, Wheelock V (2011) A Physician’s Guide to the Management of

Huntington’s Disease (Third Edition), Huntington’s Disease Society of America

Pickering SJ, Braude PR, Patel M, Burns CJ, Trussler J, Bolton V, & Minger S (2003). Preimplantation

genetic diagnosis as a novel source of embryos for stem cell research. Reproductive biomedicine

online, 7(3), 353-364.

Semaka A, Balneaves LG & Hayden MR (2013). “Grasping the Grey”: Patient Understanding and

Interpretation of an Intermediate Allele Predictive Test Result for Huntington Disease. Journal of genetic

counseling, 22(2), 200-217.

Stern HJ, Harton GL, Sisson ME, Jones SL, Fallon LA, Thorsell LP, Getlinger ME, Black SH, & Schulman JD.

Non‐disclosing preimplantation genetic diagnosis for Huntington disease. Prenat Diagn, 2002 Jun 22(6):

503-7.

Sample information sheet provided by HDSA Center of Excellence at University of California, Davis

Medical Center https://www.ucdmc.ucdavis.edu/huntingtons/genetics.html

SECTION 8

ACKNOWLEDGEMENTS

This revision of the “Genetic Testing Protocol for Huntington’s Disease” reflects the

collaboration and contributions of many people including:

Sam Frank, MD, Beth Israel Deaconess Medical Center, Boston MA

Claudia R. Adkison, JD, PhD, Atlanta GA

Robin Bennet, MS, CGC, D.Sc. Hon, University of Washington Medical Center, Seattle WA

Tom Bird, MD, University of Washington Seattle WA

Peter G. Como, PhD, Ellicott City MD

Allison Daley, MS, LCGC, MPH, Ohio State University, Columbus OH

Andrew Feigin, MD, Northwell Health, Manhasset NY

Cori Dixon- Fyle, LCSW, psychotherapist, Chicago IL

Donald Higgins, MD, Office of Specialty Care Services, Veterans Health Administration,

Washington DC

Sandra Kostyk, MD, PhD, Wexner Medical Center, Ohio State University, Columbus OH

Katie Plunkett, MS, Houston TX

Mara Sifry-Platt, MS, LCGC, Kaiser Permanente, Sacramento CA

Teresa Srajer, Moline IL

Arvind Sreedharan, Chicago IL

Teresa Tempkin, NP-C, MSN, University of California Davis Medical Center, Sacramento CA

The Huntington’s Disease Society of America is the premier nonprofit organization dedicated to

improving the lives of everyone affected by HD. From community services and education to

advocacy and research, HDSA is the world’s leader in providing help for today, hope for

tomorrow for people with HD and their families.

To learn more about Huntington’s disease and the work of the Huntington’s Disease Society of

America, visit www.hdsa.org or call (800) 345-HDSA.