NHLBI Working Group on Reporting Genetic Results
in Research Studies
Meeting Summary
Bethesda, MD
July 12, 2004
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TABLE OF CONTENTS
EXECUTIVE SUMMARY
The NHLBI Working Group on Reporting Genetic Results in Research
Studies was held July 12, 2004 in Bethesda, MD. Working group
members included experts from scientific, medical and public health
communities, and persons with expertise in ethical, legal, and
social issues. The main objective of this working group was to
discuss and make recommendations for reporting individual results
from genetic tests to participants of Heart, Lung, Blood and Sleep
research studies involving genetics.
The working group unanimously agreed that there are conditions
in which genetic results should be reported to research participants.
Genetic tests should meet three key criteria before they can be
reported to participants and their physicians: 1) The risk for
the disease should be significant, i.e. relative risk >2.0.
Variants with greater penetrance or associated with younger age
of onset should receive priority; 2) The disease should have important
health implications, i.e. fatal or substantial morbidity or should
have significant reproductive implications; and 3) Proven therapeutic
or preventive interventions should be available.
Final decisions regarding reporting of research results should
not be made by the investigator alone, and should be done only
with IRB approval after careful consideration of risks and benefits.
Genetic test results should not be reported to study participants
and their physicians as clinically valid tests unless the test(s)
was performed in a CLIA certified laboratory. If the test was
performed in a non-CLIA certified laboratory, a CLIA certified
laboratory should be sought to confirm results by redrawing a
sample and performing the test within the CLIA certified laboratory.
Results reported by a research laboratory should be identified
as ‘research’ results.
Legitimate and brief information, preferably on a single page,
should accompany test results to inform clinicians about what
to do with the genetic test/marker results.
Recommendations regarding reporting of genetic results arising
from this NHLBI working group should be coordinated and harmonized
across all DHHS agencies (NIH, FDA, CDC, HRSA, etc.) and other
federal agencies funding such research if possible.
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INTRODUCTION
Studies of heart, lung, blood and sleep disorders routinely include
genetic tests to identify new genetic risk factors in the population
and the inclusion of these tests is increasing rapidly. These
findings may provide opportunities for early detection of disease
and presymptomatic diagnosis which in turn can provide opportunities
for successful treatment and/or prevention. Research studies have
an obligation to report research findings of definitive clinical
value to study participants when the potential benefits of such
information outweigh the potential harm. Although results of genetic
tests have considerable potential for risk assessment and appropriate
targeting for preventive strategies, genetic tests usually do
not predict the development and severity complex diseases. Furthermore,
psychological and social harm as well as financial costs may result
from introducing information to research subjects and their families
about diseases that cannot be prevented or treated.
Even when a genetic mutation conferring increased risk is present,
there may be other factors such as the interaction with other
genes, variation in exposure, and population stratification, that
may make disease risk uncertain. The clinical validity of genetic
tests is also affected by small and potentially biased study populations,
low penetrance, variable expressivity, lack of understanding of
phenotypic modifiers, and ambiguous clinical endpoints. Genetic
results are likely to vary in their potential to direct prevention
and treatment, and in personal and social consequences. As a result,
the task of determining appropriate transmittal of genetic results
to research subjects will require careful consideration of a variety
of factors, including the analytic validity, clinical validity,
clinical utility, and ethical, legal, and social implications
of the results.
The goal of population-based genetic research is ultimately to
identify genetic variants that indicate increased risk of disease
or disability with particular attention to those conditions where
risk can be reduced. Although relatively few such variants may
currently be identified with certainty, it is hoped that the extensive
body of ongoing research in this area may detect many more of
such variants. The existing literature has no clear statement
on reporting such results to participants in research studies,
independent of whether public health or population screening measures
are eventually implemented. Thus, there is a need for a consensus
to identify genetic findings that have met an acceptable threshold
for individual results reporting to study participants.
The NHLBI Working Group on Reporting Genetic Results in Research
Studies was held July 12, 2004 in Bethesda, MD. Working group
members included experts from scientific, medical and public health
communities, and persons with expertise in ethical, legal, and
social issues. The main objective of this working group was to
discuss and make recommendations for reporting individual results
from genetic tests to participants of Heart, Lung, Blood and Sleep
research studies involving genetics. The meeting began with welcoming
remarks from the chair of the working group, Dr. Russell Luepker,
and presentations by each of the working group members.
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PRESENTATIONS
Dr. John Eckfeldt provided information on the Clinical Laboratory
Improvement Act (CLIA) and its later Amendments and clinical laboratory
regulations generally. The original CLIA regulations (1967) applied
only to labs involved in interstate commerce. In 1988, the Clinical
Laboratory Improvement Amendments expanded the authority to all
laboratories testing human samples for patient care regardless
of where testing is done. The following labs are excluded from
CLIA: research laboratories that do not report individual results
to participants for diagnosis, prevention, treatment, or assessment
of health, disease or impairment; National Institute of Drug Abuse
(NIDA) or Substance Abuse and Mental Health Services Administration
(SAMHSA) labs performing employee drug testing; federal laboratories
(VA, DoD, etc.); and forensic labs. CLIA applies to all samples
drawn from any patient within the U.S.; if samples collected in
the U.S. are sent outside the U.S. for testing, CLIA regulations
still apply.
There are about 75,000 laboratories with CLIA certification, of
which 50,000 are physician office laboratories. CLIA regulates
the management of specimens and the testing process including
specimen handling, requisitions, records, reports, and the referral
of specimens, quality systems, proficiency testing, and personnel
standards (www.phppo.cdc.gov/CLIA). The principal sanction for
violating CLIA is the suspension, limitation, or revocation of
a laboratory’s CLIA certificate and suspension of all Medicare/Medicaid
payments. Secondary sanctions are a directed plan of correction
and on-site monitoring at the laboratory’s expense; civil
suit and monetary penalty; and/or criminal sanctions for any individual
who is convicted of intentionally violating any CLIA requirement.
Laboratories have improved quality control procedures since CLIA
was implemented. The CDC is currently heading a working group
to amend CLIA regulations for genetic testing.
Dr. Kathleen Cranley Glass gave an overview of the ethical issues
related to reporting individual genetic results to research participants.
These include: the unchangeable nature of accurate personal genetic
information which affects the individual, family and community;
the moral obligation to protect research participants; the participants’
comprehension of the purpose of the study, the nature of their
participation and the genetic results, including the potential
for misinterpretation or exaggeration of the meaning of the results;
the risk of discrimination (individual and group); the difficulty
of drawing health/life choice conclusions from early study results
or incompletely understood data; and the potential psychosocial
effects caused by knowledge of genetic results. Dr. Glass also
stressed the ethical implications of scientific validity and clinical
relevance of genetic tests and the consequent importance of their
careful evaluation before reporting genetic research results.
In addition, pre- and post-test genetic counseling should be available
for participants who will receive personal results.
Dr. Gail Jarvik discussed reporting of genetic research results
in studies of complex disease. A genetic variant’s effect
is modified by other genes and the environment, thus are often
weak and may not reliably predict disease. Dr. Jarvik remarked
that the odds ratios for most genetic associations are not more
than 2 and many associations are not replicated in other studies.
Note that an odds ratio of 2 means a doubling of disease risk
as compared with healthy controls. The significance (absolute
risk) of an odds ratio or relative risk of 2 or more will depend
on the frequency of the disease. Thus, even if a relative risk
in the test population is very high (i.e. 100), the actual or
absolute risk of a condition with a frequency of 1/10,000 in the
general population would only be 1/100. Dr. Jarvik emphasized
that individual genetic results should only be reported when there
is proven accuracy and clinical utility. Currently, Institutional
Review Boards and individual genetic studies held primary responsibility
for deciding when disclosures should be made. She stressed the
importance of standardization or IRB rules for genetic/family
studies, including results disclosure. She also noted that informed
consent should always be requested with an option to opt in/out
of receiving information and that the person disclosing the genetic
results should be trained to provide genetic counseling.
Dr. Michael Klag gave an overview of perspectives in reporting
genetic results in his research studies and suggested points to
consider when deciding to communicate genetic results. Two examples
were given, one of participants not asking for genetic results
and the other of a participant writing a letter requesting that
he be informed of genetic results even though he understood that
the clinical utility was unproven and clinical judgments on the
basis of the results would be questionable. Dr. Klag suggested
that the disease risk, the complexity of the trait, the degree
of penetrance, age of onset, disease severity, reproductive implications,
and availability of therapeutic or preventive interventions be
considered when deciding to report genetic results to individuals.
Dr. Klag also suggested that a written document explaining the
implications of the results be provided to the participant and/or
to the participant’s physician to assist in interpreting
risks for the participant and family members. He noted that IRBs
in his institution are leaning toward the view that, in some situations,
disclosure of non-CLIA certified results will be more ethical
than non-disclosure.
Dr. Gregory Koski gave an overview of the decision-making process
of the Framingham Heart Study’s Ethics Advisory Board in
deciding whether to report research results to participants. He
explained that many policies are designed to protect only the
individual, but there were repercussions for the family as well.
He noted that non-genetic tests and genetic tests have similar
implications for risks to the participant, but the genetic information
is often considered to be unique in that it also provides information
on parents, offspring, siblings and the community. He also noted
that genetics is often considered to be unique because of its
predictive value but often such predictions are far less definitive
than those obtained by more routine clinical tests. Currently
there are social and legal reforms in the area of genetic discrimination
that may simplify the interpretation of risks and benefits of
reporting.
Dr. Russell Luepker discussed the rationale in reporting genetic
research results to individuals including the unique complexities
of population studies, ethical considerations and the negative
effects of reporting results. Dr. Luepker gave suggestions of
items that should be included in the informed consent form before
genetic results may be reported and reiterated that analytic validity,
clinical validity and clinical utility should be taken into account
before deciding to give genetic research results back to the participant.
He also talked about the huge impact that the media hype surrounding
the human genome project has had on the public and its understanding
of genetic determinism. Dr. Luepker agreed that proven interventions
need to be available before a specific genetic test is reported
to the participant.
Dr. Arno Motulsky discussed the ambiguous meaning of ‘genetic’
results and general considerations when deciding to disclose individual
results in genetic studies. He explained that many tests other
than DNA tests may provide results that portray the underlying
genotype. Examples of these tests include tests for hemoglobinopathies
(HbS), enzyme deficiencies (G6PD), and clotting protein abnormalities
(hemophilia). He also explained that a test generally considered
to be non-genetic such as a cholesterol level usually has strong
genetic determinants in addition to environmental factors (diet).
Dr. Motulsky noted that over 1600 Mendelian traits with a definitive
molecular basis have been found, yet only about 10 genes had been
detected for human complex disease traits (Glazier et al. 2002).
He suggested that the magnitude of the research study, the type
of contact with the study subjects (direct or indirect), the certainty
of the new information affecting health and disease, the qualifications
of the investigators, and the availability of referrals to outside
physicians be considered when deciding to report genetic results
to research participants. He also noted that informed consent
before testing should allow participants to decline to receive
results.
Dr. Benjamin Wilfond gave his perspective on the criteria for
the discretionary decision of disclosing genetic results in research
studies. He described situations in which disclosing genetic research
results would be prohibitive, discretionary, and obligatory. Dr.
Wilfond remarked that the relationship of validity to benefits
and harms is complex when deciding to report results. Uncertain
data can be beneficial because it can give information regarding
risk although the uncertainty of results can also exaggerate harms.
He noted that reasons for disclosing results include participants’
contribution to research and collaboration and trust of communities
in which the research is performed. He also suggested that simply
disclosing results may not be sufficient and that providing intervention
or remediation may also be needed. Dr. Wilfond suggested ways
to improve the benefit/harm ratio of result disclosure including
consenting for disclosure/non-disclosure, ensuring analytic validity,
communicating results effectively by including health care providers
and follow-up support, and reviewing of the research protocol
and disclosure guidelines by the study’s institutional review
board.
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GUIDELINES FOR REPORTING GENETIC RESEARCH RESULTS
The working group unanimously agreed that there are conditions
in which genetic results should be reported to research participants.
Guidelines and criteria for analytic validity, clinical validity,
clinical utility and ethical, legal, social issues were discussed.
Analytic Validity
Dr. Eckfeldt began this discussion by acknowledging multiple facets
of diagnostic accuracy, both pre- and post-analytical. He noted
that most proficiency test programs identified most errors made
in laboratories as clerical. He suggested that genetic results
that are reported back to subjects should be performed in a CLIA
certified laboratory and if available, the laboratory should also
be certified to perform the particular test. Dr. Eckfeldt explained
that certification is not specifically available for many genetic
tests because the genetic mutations are relatively rare and usually
about 50 or more laboratories must be performing a given genetic
test before the typical proficiency testing agencies will offer
a proficiency testing program for the given genetic test. Working
group members agreed that research investigators should give a
study participant guidance on where and how they might seek clinical
care when reporting results. However, it was noted that some participants
may not have insurance and/or be able to afford clinical care
and that a specialist may not be in reasonable proximity.
Clinical Validity
Dr. Motulsky introduced the discussion by defining clinical validity
as the accuracy by which the test predicts clinical outcome. He
noted that sensitivity (the probability that a person positive
for a test will get disease and specificity (the probability that
the test will be negative in people without disease) are evaluated
when assessing clinical validity. Dr. Motulsky noted that the
genetic and epidemiologic factors affecting clinical validity
include analytical validity of genotyping, presence of genetic
and other modifiers, heterogeneity in etiology, statistical power
of studies used to identify genetic associations, selection bias,
and gene-environment interaction. Clinical factors affecting clinical
validity are penetrance of genotype, variable expressivity, phenotype
description, environmental factors, and various clinical or other
endpoints. The group discussed genetic markers that are currently
clinically valid and criteria by which to judge new markers. They
suggested that tests currently offered in clinical CLIA certified
laboratories are a good start to identifying clinically valid
tests.
Clinical Utility
Dr. Klag began the discussion by stating that the issue of the
magnitude or risk and outcome is essential. He also suggested
that the determination of clinical utility includes the availability
and effectiveness of an intervention. The group noted that the
physician’s understanding of results can affect the utility
of the results and suggested that the principal investigator include
a one page summary sheet, written for lay persons, to educate
physicians about the results. The group agreed that a relative
risk of greater than 2.0 with consideration of a significant absolute
risk should be met before results should be reported to the research
participant since in many studies, early results of increased
relative risk cannot be replicated.
Ethical, Legal, and Social Issues
Dr. Glass started the discussion by stating that consideration
should be given to how genetic results will be reported to participants
and how genetic counseling will be implemented. The group agreed
that it was the obligation of the investigational team to have
a consultant who understands the genetic information and possible
benefits and harms explain possible findings as well as the actual
genetic results and their meaning to the participant if such expertise
is not available within the investigative team. The group also
agreed that a research study is obligated to provide reportable
results to participants as long as the study is active, even if
primary data collection is finished. The group was less clear
on the appropriate intensity of efforts to contact participants
(that is, is one letter or phone call enough?), or on the responsibilities
to participants once contact has ceased, particularly if some
contact information is still available. NHLBI was advised to seek
additional legal advice on this issue.
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RECOMMENDATIONS
- A primary finding of this group was that some genetic test
results from research studies may be offered to subjects, using
similar guidelines as other tests, such as cholesterol levels,
which are routinely shared with subjects. There are conditions
in which genetic results should be offered to study participants.
Examples include homozygous Factor V Leiden, cystic fibrosis transmembrane
conductance regulator (CFTR) and breast cancer BRCA1/BRCA2 mutations.
- In general, genetic markers should not be withheld if they
meet key criteria described below.
- Genetic tests should meet three key criteria before they can
be reported to participants and their physicians:
a. The risk for the disease should be significant, i.e. relative
risk >2.0. Variants with greater penetrance or associated with
younger age of onset should receive priority.
AND
b. The disease should have important health implications, i.e.
fatal or substantial morbidity or should have significant reproductive
implications.
AND
c. Proven therapeutic or preventive interventions should be available.
- Genetic test results should not be reported to study participants
and their physicians as clinically valid tests unless the test(s)
was performed in a CLIA certified laboratory. If the test was
performed in a non-CLIA certified laboratory, a CLIA certified
laboratory should be sought to confirm results by redrawing a
sample and performing the test within the CLIA certified laboratory.
If a genetic test is performed only in one research laboratory
and thus is unable to be performed in a CLIA certified laboratory,
the test needs to be run by two different methods and/or the research
laboratory should work under direct supervision of a CLIA certified
laboratory to confirm results. Results reported by a research
laboratory should be identified as ‘research’ results.
- Final decisions regarding reporting of research results should
not be made by the investigator alone, and should be done only
with IRB approval after careful consideration of risks and benefits.
- A process should be developed for educating non-geneticist
members of the research team (investigators, IRB members, subject
advocates, etc.) on the difference between highly penetrant monogenic
genetic diseases as compared to genes of small effect contributing
to complex traits. Such understanding is required for the evaluation
of the risks and benefits of reporting results to participants.
- NHLBI should develop a list of widely available genetic tests
and a subgroup of the working group will suggest those appropriate
for consideration for reporting. This list cannot be considered
inclusive, given the changing nature of the field, but should
provide examples and guidance for deciding which tests should
be offered. These suggestions should be reviewed by investigators
from individual studies for appropriateness for reporting in their
study. This process should be repeated on a periodic basis by
a group with sufficient expertise to judge the evolving scientific
foundation for reporting these results.
- Appendix A lists examples of genetic tests/markers which should
or should not be reported. Appendix B lists genetic diseases in
which clinical testing is available in more than two U.S. laboratories
(supplied by GeneTests).
- Consent forms should address results with personal implications
and reproductive implications separately, as by a two part question
such as, “We will be studying genes that affect cardiovascular
disease but may find other genetic disorders. Do you want results
reported that have significant health implications for yourself
or your family members? Reproductive implications for yourself
or your family?” Persons administering informed consent
for genetic tests should be trained to explain the potential implications
of reporting, both personal and reproductive.
- A counselor/consultant should be provided to explain the nature
of the study, implications of participation, and the potential
relevance of the genetic results, including any risks of harm
or potential for benefits for participants, their families or
communities; this person need not be a licensed genetic counselor,
but must be properly qualified by training and experience to execute
this responsibility appropriately.
- Legitimate and brief information, preferably on a single page,
should accompany test results to inform clinicians about what
to do with the genetic test/marker results. Ideally, these information
sheets should be standardized and available from a repository,
perhaps as part of a website relating this information. Findings
with reproductive implications, including implications for the
relatives or offspring of the subject, should follow the same
guidelines as other tests.
- Standard of care/clinical practice guidelines should be followed.
- Recommendations regarding reporting of genetic results arising
from this NHLBI working group should be coordinated and harmonized
across all DHHS agencies (NIH, FDA, CDC, HRSA, etc.) and other
federal agencies funding such research if possible.
- Consensus panels by professional organizations (American Society
of Human Genetics, American College of Medical Genetics, etc.)
may be valuable in establishing or reviewing the criteria, so
that recommendations developed by NIH are not viewed as designed
to serve its research agenda.
- DHHS should issue formal, uniform guidance for IRBs, institutions,
investigators and sponsors with respect to best practices for
testing and reporting genetic results in human research studies.
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MEETING ROSTER
Reporting Genetic Results in Research Studies Working Group Meeting
July 12, 2004
MEMBERS
Russell V. Luepker, M.D., M.S., Chair
Mayo Professor
Division of Epidemiology
School of Public Health
University of Minnesota
1300 S. Second St.
Minneapolis, MN, 55454, USA
(612) 624-6362 office
(612) 624-0315 fax
luepk001@umn.edu
John Eckfeldt, M.D.,Ph.D.
Professor
Departments of Laboratory Medicine and Pathology
University of Minnesota
763-1 Mayo
420 Delaware Street SE
Minneapolis, MN 55455
(612) 626-3176 office
(612) 626-3176 fax
eckfe001@umn.edu
Kathleen Cranley Glass, D.C.L.
Director, Biomedical Ethics Unit
Associate Professor, Departments of
Human Genetics & Pediatrics
McGill University
3647 Peel Street
Montreal, Quebec H3A 1X1
(514) 398-6945 office
(514) 398-8349 fax
kathleen.glass@mcgill.ca
Gail P. Jarvik, M.D., Ph.D.
Associate Professor of Medicine
Division of Medical Genetics
University of Washington Med Center Box 357720
Seattle, WA 98195-7720
(206) 685-9069 office
(206) 616-7186 fax
pair@u.washington.edu
Michael Klag, M.D.
Professor
Department of Internal Medicine
School of Medicine
John’s Hopkins University
Building 2024, Suite 2-200
600 North Wolfe St.
Baltimore, MD 21287-1824
(410) 955-0496 office
(410) 955-0315 fax
mklag@jhmi.edu
Greg Koski, M.D., Ph.D.
Associate Professor
Department of Anesthesia
Massachusetts General Hospital
32 Fruit Street Clinic 3
Boston, MA 02114
(617) 726-8980 office
(617) 726-5985 fax
gkoski@partners.org
Arno Motulsky, M.D.
Professor
Depts of Medicine & Genome Sciences
University of Washington
Health Sciences Bldg K-343A
Seattle, WA 98195
(206) 543-3593 ext. 357730 office
(206) 685-7301 fax
agmot@u.washington.edu
Benjamin Wilfond, M.D.
Medical Genetics Branch, NHGRI
National Institutes of Health
Bldg 10, Rm. 1C-118
Bethesda, MD. 20892
(301) 435-8728 office
(301) 496-0760 fax
wilfond@nhgri.nih.gov
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Appendix A
Examples of genetic test results that should be reported to subjects:
Example 1: Mutations causing Marfan syndrome. Marfan syndrome
is an autosomal dominant condition caused by mutations in the
fibrillin gene FBN1 gene (chromosomal locus 15q21.1). The disorder
is characterized by ophthalmologic and skeletal physical findings.
Cardiac findings include a predisposition for aortic tear and
rupture, which can be fatal. Ultrasound diagnosis of a dilated
aortic root leads to monitoring and prophylactic surgery, which
is life-saving.
Characteristics that make a Marfan syndrome genetic tests a good
example of genetic information that should be shared with an interested
subject are 1) That the penetrance approaches 100%; 2) Medical
care can prevent death/complications, 3) the risk is well documented
in multiple studies.
An additional feature that make this an important result to share
is that the affected individual be may be undiagnosed, particularly
among the 25% of cases that are estimated to be new mutations,
without a family history to increase clinical suspicion of the
diagnosis.
This example also illustrates some of the limitations of genetic
testing. First, over 200 mutations in the FBN1 gene have been
reported to cause Marfan syndrome or associated, milder phenotypes.
In 2004 only 70-90% of subjects with Marfan syndrome have a positive
test (Marfan mutation identified). A negative test (i.e. no Marfan
mutation detected) therefore does not rule out the diagnosis.
More detailed information can be found at. http://www.geneclinics.org/
Example 2: Individuals homozygous for Factor V Leiden deficiency
or heterozygotes who have an additional propensity to thrombophilia.
The factor V Leiden mutation (F5G1691A) results in an identical
amino acid substitution. This results in a slight increase in
venous thrombosis in heterozygotes (RR 4-8), but a marked increase
in the risk of venous thrombosis in homozygotes (RR ~80). Among
heterozygotes, the presence of other inherited pro-coagulant tendencies
such as protein C, protein S, and antithrombin deficiencies; prothrombin
(PT) gene mutation, and elevated homocysteine increases the risk
for thrombosis. Similarly, environmental factors such as estrogen
exposure (use of oral contraceptives, hormone replacement therapy,
and pregnancy) and surgery predispose to thrombosis. Known factor
V Leiden allele carriers have their estrogen and surgery exposures
carefully managed and may be treated longer for diagnosed thrombosis
than other individuals.
Characteristics that make Factor V Leiden homozygotes a good example
of genetic information that should be shared with an interested
subject are: 1) dramatically increased risk of thrombosis; and
2) the ability to avoid or manage exposure to decrease morbidity
associated with the thromboses, 3) this is a single mutation that
can be accurately and cheaply tested by genetic techniques 4)
the risk is well documented in multiple studies.
The question of notifying heterozygotes is less straightforward.
Heterozygotes with additional known risk factors, such a PT mutations,
should be given their genetic testing results. However, in the
absence of other known pro-coagulant factors, the actual increased
risk is small and must be weighed against the risk of hemorrhage
from anticoagulant therapy. Further expert review should be considered
to determine whether genetic test results should be disclosed
for heterozygotes.
Examples of genetic test results that should not be reported to
subjects:
1) The results of genetic tests that demonstrate non-paternity
should not be shared with family members. Although there is a
conceptual advantage of identifying true fathers that have useful
genetic information for the offspring affected, this does not
outweigh the substantial psychological impact to families risked
by sharing this information.
2) An example of results that we do not support sharing with willing
subjects is that of APOE. There are 3 common APOE alleles, 2,
3, and 4, and the 6 resulting genotypes have varying risk of Alzheimer
disease. The risk for the 3/4 heterozygotes (`25% of Caucasians)
is 2-3-fold increased and for homozygotes (1-2% of the Caucasian
population) is substantially increased, perhaps 30-fold. However,
APOE gene testing is not used clinically, even in patients at
increased risk for Alzheimer disease. This is due to 1) the fact
the outcome for a particular genotype is not known, 2) the current
lack of a preventive strategy, and 3) the anxiety generated by
a positive test in the absence of a benefit, particularly given
the generally poor public understanding of the meaning of a risk
factor, vs. presence of a disease gene. The same reasons that
keep APOE from clinical use should result in scientists NOT sharing
this result with subjects. Additionally, care providers of research
study participants may be poorly prepared to interpret these results.
Examples of genetic tests which should be further considered to
determine recommendations for release of results to:
1) Factor V Leiden heterozygotes, as discussed above.
2) Hemochromatosis homozygotes.
3) Alpha 1 antitrypsin deficiency homozygotes
4) Cystic fibrosis (CFTR) mutation carriers (heterozygotes).
Examples 1-2 indicate disorders where only a small percentage
of individuals with the genotype will become symptomatic. Example
4 has a risk of having an affected child in mating with another
carrier.
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Appendix B
Genetic diseases for which clinical testing is available in more
than two U.S. laboratories -- Sorted alphabetically. (Heart, Lung,
Blood and Sleep disorders are in bold)
| Disease Name |
Number of Labs |
| 17-Linked
Lissencephaly |
32 |
| 1p36
Deletion Syndrome |
8 |
| 21-Hydroxylase
Deficiency |
7 |
| 22q11.2
Deletion Syndrome |
37 |
| 3-Hydroxy-3-Methylglutaryl-Coenzyme
A Lyase Deficiency |
9 |
| 3-Methylcrotonyl-CoA
Carboxylase Deficiency |
8 |
| 3-Methylglutaconic
Aciduria Type 1 |
9 |
| 5-Oxoprolinuria |
5 |
| ARX-Related
Disorders |
3 |
| Achondroplasia |
10 |
| Adrenoleukodystrophy,
X-Linked |
4 |
| Alagille
Syndrome |
6 |
| Alkaptonuria |
3 |
| Alpha-1-Antitrypsin
Deficiency |
9 |
| Alpha-Mannosidosis |
11 |
| Alpha-Thalassemia |
10 |
| Angelman
Syndrome |
72 |
| Arginase
Deficiency |
11 |
| Argininosuccinicaciduria |
10 |
| Aspartylglycosaminuria |
3 |
| BRCA1
Hereditary Breast/Ovarian Cancer |
9 |
| BRCA2
Hereditary Breast/Ovarian Cancer |
8 |
| Beckwith-Wiedemann
Syndrome |
9 |
| Beta-Mannosidosis |
6 |
| Beta-Thalassemia |
7 |
| Biotinidase
Deficiency |
7 |
| Bloom
Syndrome |
17 |
| CFTR-Related
Disorders |
62 |
| CLN2-Related
Neuronal Ceroid-Lipofuscinosis |
3 |
| Canavan
Disease |
33 |
| Carbamoylphosphate
Synthetase I Deficiency |
6 |
| Carnitine
Deficiency, Systemic |
13 |
| Carnitine
Palmitoyltransferase IA (liver) Deficiency |
4 |
| Carnitine
Palmitoyltransferase II Deficiency |
8 |
| Carnitine-Acylcarnitine
Translocase Deficiency |
5 |
| Charcot-Marie-Tooth
Neuropathy Type 1A |
4 |
| Charcot-Marie-Tooth
Neuropathy Type 2B1 |
3 |
| Citrullinemia
Type I |
13 |
| Colon
Cancer (APC I1307K related) |
4 |
| Congenital
Disorders of Glycosylation |
4 |
| Creatine
Deficiency Syndrome, X-Linked |
3 |
| Cri
du Chat Syndrome |
28 |
| Cystinosis |
3 |
| Cystinuria |
8 |
| DFNB
4 |
4 |
| DRPLA |
10 |
| Diabetes
Mellitus, Transient Neonatal |
4 |
| Diabetes
and Hearing Loss |
6 |
| Down
Syndrome Critical Region |
3 |
| Duchenne/Becker
Muscular Dystrophy |
26 |
| Early-Onset
Primary Dystonia (DYT1) |
8 |
| Emery-Dreifuss
Muscular Dystrophy, Autosomal |
3 |
| FANCC-Related
Fanconi Anemia |
13 |
| FGFR1-Related
Craniosynostosis Syndromes |
6 |
| FGFR2-Related
Craniosynostosis Syndromes |
7 |
| FGFR3-Related
Craniosynostosis Syndromes |
7 |
| FRAXE
Syndrome |
5 |
| Fabry
Disease |
14 |
| Facioscapulohumeral
Muscular Dystrophy |
4 |
| Factor
V Leiden Thrombophilia |
83 |
| Factor
V R2 Mutation Thrombophilia |
5 |
| Familial
Adenomatous Polyposis |
9 |
| Familial
Dysautonomia |
13 |
| Familial
Malignant Melanoma |
3 |
| Familial
Mediterranean Fever |
3 |
| Familial
Nonchromaffin Paragangliomas |
3 |
| Familial
Partial Lipodystrophy, Dunnigan Type |
3 |
| Fanconi
Anemia |
4 |
| Fatal
Infantile Cardioencephalopathy due to COX Deficiency |
3 |
| Fatty
Acid Oxidation Disorders |
3 |
| Fragile
X Syndrome |
73 |
| Free
Sialic Acid Storage Disorders |
4 |
| Friedreich
Ataxia |
16 |
| Fucosidosis |
11 |
| Fumarate
Hydratase Deficiency |
4 |
| GJB2-Related
DFNA 3 Nonsyndromic Hearing Loss and Deafness |
11 |
| GJB2-Related
DFNB 1 Nonsyndromic Hearing Loss and Deafness |
22 |
| GJB6-Related
DFNB 1 Nonsyndromic Hearing Loss and Deafness |
7 |
| GM1
Gangliosidosis |
11 |
| GTP
Cyclohydrolase 1-Deficient DRD |
3 |
| Galactosemia |
11 |
| Gaucher
Disease |
27 |
| Glutaricacidemia
Type 1 |
11 |
| Glutaricacidemia
Type 2 |
11 |
| Glycerol
Kinase Deficiency |
9 |
| Glycine
Encephalopathy |
7 |
| Glycogen
Storage Disease Type 1a |
6 |
| Glycogen
Storage Disease Type II |
11 |
| Glycogen
Storage Disease Type V |
5 |
| Glycogen
Storage Disease Type VII |
4 |
| Guanidinoacetate
Methyltransferase Deficiency |
3 |
| HFE-
Associated Hereditary Hemochromatosis |
53 |
| Hartnup
Disease |
4 |
| Hemoglobin
Constant Spring |
3 |
| Hemoglobin
E |
3 |
| Hemoglobin
S Beta-Thalassemia |
5 |
| Hemoglobin
SC |
14 |
| Hemoglobin
SS |
23 |
| Hemophilia
A |
14 |
| Hemophilia
B |
4 |
| Hereditary
Fructose Intolerance |
4 |
| Hereditary
Neuropathy with Liability to Pressure Palsies |
5 |
| Hereditary
Non-Polyposis Colon Cancer |
10 |
| Hereditary
Pancreatitis |
5 |
| Hexosaminidase
A Deficiency |
34 |
| Histidinemia |
3 |
| Holocarboxylase
Synthetase Deficiency |
3 |
| Homocystinuria
Caused by Cystathionine Beta-Synthase Deficiency |
15 |
| Huntington
Disease |
30 |
| Hutchinson-Gilford
Progeria Syndrome |
4 |
| Hyperlipoproteinemia
Type III |
3 |
| Hyperlysinemia |
5 |
| Hyperornithinemia-Hyperammonemia-Homocitrullinuria
Syndrome |
3 |
| Hypochondroplasia |
8 |
| Ichthyosis,
X-Linked |
26 |
| Infantile
Myopathy and Lactic Acidosis (Fatal and Non-Fatal
Forms) |
6 |
| Isolated
Persistent Hypermethioninemia |
4 |
| Isovaleric
Acidemia |
10 |
| Kallmann
Syndrome, X-Linked |
23 |
| Ketothiolase
Deficiency |
4 |
| Krabbe
Disease |
7 |
| LGMD1B |
3 |
| LMNA-Related
Dilated Cardiomyopathy |
3 |
| Langer-Giedion
Syndrome |
4 |
| Leber
Hereditary Optic Neuropathy |
14 |
| Li-Fraumeni
Syndrome |
7 |
| Long
Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency |
16 |
| Long
Chain Acyl-CoA Dehydrogenase Deficiency |
4 |
| MELAS |
18 |
| MERRF |
18 |
| MTHFR
Deficiency |
3 |
| MTHFR
Thermolabile Variant |
52 |
| MTRNR1-Related
Hearing Loss and Deafness |
8 |
| MTTS1-Related
Hearing Loss and Deafness |
3 |
| Malonyl-CoA
Decarboxylase Deficiency |
3 |
| Mandibuloacral
Dysplasia |
3 |
| Maple
Syrup Urine Disease |
14 |
| Marfan
Syndrome |
5 |
| Medium
Chain Acyl-Coenzyme A Dehydrogenase Deficiency |
44 |
| Metachromatic
Leukodystrophy |
8 |
| Methylmalonicaciduria |
11 |
| Mevalonicaciduria |
4 |
| Mitochondrial
DNA Deletion Syndromes |
10 |
| Mitochondrial
DNA-Associated Leigh Syndrome and NARP |
16 |
| Mitochondrial
Disorders |
4 |
| Mucolipidosis
I |
7 |
| Mucolipidosis
II |
6 |
| Mucolipidosis
III |
4 |
| Mucolipidosis
IV |
7 |
| Mucopolysaccharidosis
Type I |
15 |
| Mucopolysaccharidosis
Type II |
10 |
| Mucopolysaccharidosis
Type IIIA |
7 |
| Mucopolysaccharidosis
Type IIIB |
12 |
| Mucopolysaccharidosis
Type IIIC |
7 |
| Mucopolysaccharidosis
Type IIID |
6 |
| Mucopolysaccharidosis
Type IVA |
7 |
| Mucopolysaccharidosis
Type IVB |
10 |
| Mucopolysaccharidosis
Type VI |
13 |
| Mucopolysaccharidosis
Type VII |
12 |
| Multiple
Endocrine Neoplasia Type 1 |
3 |
| Multiple
Endocrine Neoplasia Type 2 |
13 |
| Multiple
Exostoses, Type I |
3 |
| Multiple
Exostoses, Type II |
3 |
| Myotonic
Dystrophy Type 1 |
25 |
| Neurofibromatosis
1 |
10 |
| Niemann-Pick
Disease Due to Sphingomyelinase Deficiency |
17 |
| Noonan
Syndrome |
6 |
| Ornithine
Aminotransferase Deficiency |
6 |
| Ornithine
Transcarbamylase Deficiency |
12 |
| Oroticaciduria |
3 |
| PLP1-Related
Disorders |
3 |
| Pendred
Syndrome |
5 |
| Pervasive
Developmental Disorders |
3 |
| Phenylalanine
Hydroxylase Deficiency |
19 |
| Plasminogen
Activator Inhibitor I |
5 |
| Polycystic
Kidney Disease 1, Autosomal Dominant |
5 |
| Prader-Willi
Syndrome |
76 |
| Propionic
Acidemia |
11 |
| Prothrombin
G20210A Thrombophilia |
71 |
| Refsum
Disease |
4 |
| Retinoblastoma |
4 |
| Rett
Syndrome |
12 |
| Rubinstein-Taybi
Syndrome |
5 |
| Russell-Silver
Syndrome |
5 |
| SOD1-Related
Amyotrophic Lateral Sclerosis |
4 |
| Saethre-Chotzen
Syndrome |
5 |
| Sandhoff
Disease |
10 |
| Schindler
Disease |
3 |
| Short
Chain Acyl-CoA Dehydrogenase Deficiency 1 |
0 |
| Smith-Lemli-Opitz
Syndrome |
6 |
| Smith-Magenis
Syndrome |
3 |
| Sotos
Syndrome |
4 |
| Spinal
Muscular Atrophy |
23 |
| Spinal
and Bulbar Muscular Atrophy |
13 |
| Spinocerebellar
Ataxia Type 1 |
8 |
| Spinocerebellar
Ataxia Type 2 |
9 |
| Spinocerebellar
Ataxia Type 3 |
9 |
| Spinocerebellar
Ataxia Type 6 |
8 |
| Spinocerebellar
Ataxia Type 7 |
8 |
| Spinocerebellar
Ataxia Type 8 |
4 |
| Spinocerebellar
Ataxia Type10 |
3 |
| Succinic
Semialdehyde Dehydrogenase Deficiency |
4 |
| Thanatophoric
Dysplasia |
4 |
| Trichorhinophalangeal
Syndrome Type I |
3 |
| Tuberous
Sclerosis 2 |
3 |
| Tyrosinemia
Type I |
9 |
| Tyrosinemia
Type II |
8 |
| Tyrosinemia
Type III |
3 |
| Very
Long Chain Acyl-CoA Dehydrogenase Deficiency |
7 |
| Von
Hippel-Lindau Syndrome |
3 |
| Von
Willebrand Disease |
4 |
| Williams
Syndrome |
36 |
| Wolf-Hirschhorn
Syndrome |
25 |
| XX
Male Syndrome |
26 |
| XY
Gonadal Dysgenesis |
26 |
| Y
Chromosome Infertility |
13 |
| Zellweger
Syndrome Spectrum |
4 |
Last updated: September 30, 2004
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Department of Health
and Human Services
National
Institutes of Health
National Heart, Lung, and Blood
Institute