Genetic Susceptibility to Birth Defects in Humans:
TERATOLOGY 61:17-20 (2000)
Genetic Susceptibility to Birth Defects in Humans:
From Gene Discovery to Public Health Action
MUIN J. KHOURY
Office of Genetics and Disease Prevention, Centers for Disease Control and Prevention, Atlanta,
ADVANCES IN dromes. Increasingly, more common gene
HUMAN GENETIC RESEARCH variants have been associated with the risk for
common birth defects. For example, the me-
With the relentless progress of the Human thylene tetrahydrofolate reductase (MTHFR)
Genome Project, by the year 2001, most--if not polymorphism has been associated with the
all--of the estimated 100,000 human genes will risk for neural tube defects (Posey, ‘96). The
have been found (Collins, ‘98). Close to 10,000 interaction between gene variants at multiple
genes have already been cataloged (Online loci with environmental exposures is likely to
Mendelian Inheritance in Man, ‘98), and tests explain most common defects such as neural
for more than 700 genes are already available tube defects, oral clefts, and congenital car-
in medical practice (Pagon, ‘98). The genes diovascular malformations.
identified thus far range from those associated As a result of genetic research, information
with rare metabolic disorders to those associ- on differential genetic susceptibility to birth
ated with common diseases including cancer defects will be accumulating. Ideally, infor-
and adult-onset conditions. Genetic variants mation on genetic susceptibility to birth de-
confer increased susceptibility to a variety of fects will be used to target beneficial interven-
environmental factors (including chemical, tions that reduce the risk for birth defects (e.g.,
infectious, physical, social, psychological, be- nutritional interventions such as folic acid), or
havioral, and nutritional factors), thus increas- to avoid certain pregnancy exposures for indi-
ing the risk of carriers for many diseases in- viduals at greatest risk (e.g., avoiding certain
cluding birth defects. anti-epileptic drugs on the basis of a person’s
Although birth defects remain the leading genetic metabolic profile). However, complex
cause of infant mortality in the United States ethical, legal, and social issues are already be-
(CDC, ‘98), the causes of most birth defects ing raised about the pitfalls of genetic testing
remain elusive. Nevertheless, an increasing in general (Lewontin, ‘96). The effective use
number of clinical and epidemiologic studies of genetic knowledge and technology is be-
are beginning to identify risk factors for birth coming a crucial challenge to the public health
defects (Khoury, ‘95). Over the last two dec- community. The manner with which genetic
ades, numerous investigators have identified information can be used to promote health and
malformations associated with rare single-gene prevent disease and disability, especially birth
disorders. Table 1 shows the results of a quick defects, has scarcely been explored. Informa-
search of the Online Mendelian Inheritance in
Address for correspondence:
Man Catalog on the Internet. As can be seen, Muin J. Khoury, MD, PhD, Office of Genetics and
dozens of genes (mostly in a few families) have Disease Prevention, Centers for Disease Control and
been reported to be associated with a variety Prevention, 4770 Buford Hwy, Mail Stop K28, Atlanta,
birth defects leading to malformation syn- Georgia 30341
GENETIC SUSCEPTIBILITY TO BIRTH DEFECTS 18
tion is lacking about the population distribution ferent communities. The plan assumes that
of genotypes associated with birth defects, the much of the delivery of genetic tests and ser-
benefits and risks of genetic testing, and the vices will be done within the context of the
efficacy of interventions. The complex and evolving health care system, including by
controversial issues that have emerged--about managed care organizations, rather than by
quality assurance for laboratory testing, rapid public health agencies. Public health agencies,
commercialization of genetic tests, lack of however, will have an increasing role in as-
availability and access to effective and accept- sessing the health needs of populations, ensur-
able interventions, and potential discrimination ing the quality of genetic tests and services,
against and stigmatization of individuals and and evaluating the impact of interventions.
groups--call for public health leadership (CDC, The framework for the role of genetics in
‘97). public health is based on an extension of the
Institute of Medicine model of the future of
A FRAMEWORK FOR THE IMPACT OF public health (IOM, ‘88). This extended
GENE DISCOVERIES ON PUBLIC framework identifies four essential compo-
HEALTH ACTION nents of public health genetics programs:
1) Public health assessment using surveil-
In 1997, the Centers for Disease Control and lance and population-based epidemiologic
Prevention created the Office of Genetics and studies to assess how risk for disease and
Disease Prevention to highlight the emerging disability in different populations is influ-
role of genetics in the practice of public health enced by the interaction of human genetic
in the United States, and to provide internal variation with modifiable risk factors.
coordination and promote external partnerships 2) Evaluation of genetic testing policies and
in activities related to genetics and disease pre- of the quality of genetic testing to ensure
vention and health promotion. This action was the appropriateness and quality of popula-
recommended in an agency-wide strategic plan tion-based genetic testing.
that outlines a conceptual framework for a pub- 3) Development, implementation, and
lic health program in genetics (CDC, ‘97). The evaluation of public health programs that
strategic plan is based on the assumption that, ensure that genetic tests and services are
broadly defined, virtually all human diseases of integrated into population-based interven-
important public health impact are the result of tions that promote health and prevent dis-
the interaction between human genetic varia- ease and disability.
tion and the environment. It is also based on the 4) Communication and information dissemi-
assumption that the use of genetic information nation to provide timely and accurate in-
in public health is appropriate in diagnosing, formation to both the general public and
treating, and preventing disease, disability, and professional audiences on the role of ge-
death among people who inherit specific geno- netics in the promotion of health and the
types. Prevention includes the use of medical, prevention of disease and disability.
behavioral, and environmental interventions to In order for these activities to be done, three
reduce the risk for disease among people sus- cross-cutting critical issues that can affect
ceptible because of their genetic makeup. The each program component need to be ad-
plan supports the responsible use of genetic dressed: partnerships and coordination; ethi-
tests and services, including adequate family cal, legal, and social issues (e.g., using stored
history assessment and genetic counseling, for samples such as newborn blood spots for con-
promoting health and preventing disease in dif- ducting large-scale epidemiologic studies of
GENETIC SUSCEPTIBILITY TO BIRTH DEFECTS 19
birth defects etiology); and training of the pub- semination of population-based human ge-
lic health workforce and education of the gen- nome epidemiologic information. The goals of
eral public. HuGE Net are to 1) establish an information-
In the field of birth defects, the existing exchange network that promotes global col-
model of public health assessment involves laboration in the development and dissemina-
conducting surveillance for birth defects and tion of peer-reviewed epidemiologic informa-
population-based epidemiologic studies to find tion on human genes; 2) develop an updated
the causes of those birth defects. This model and accessible knowledge base on the World
can easily be extended to begin looking simul- Wide Web; and 3) promote the use of this
taneously at genetic risk factors along with en- knowledge base by health care providers, re-
vironmental factors to explain the complex eti- searchers, industry, government, and the pub-
ology of the most common malformations. In lic for making decisions involving the use of
fact, this work is currently been done collabora- genetic tests and services for disease preven-
tively by several birth defects surveillance pro- tion and health promotion.
grams and members of the National Birth De- The term human genome epidemiology
fects Prevention Network (NBDPN, ‘97), as (HuGE) denotes an evolving field of inquiry
well as by birth defects registries and academic that uses systematic applications of epidemi-
institutions from around the world. In particu- ologic methods and approaches in popula-
lar, case-control studies that use data from tion-based studies of the impact of human ge-
population-based birth defects registries will netic variation on health and disease. The
prove to be exceptionally useful for gathering spectrum of topics addressed in human ge-
information about the effect of gene- nome epidemiology range from basic to ap-
environment interactions on the risk for birth plied population-based research on discovered
defects, especially for rare defects (Khoury, human genes. Human genone epidemiology
‘94). Alternatively, large-scale collaborative can be used to:
prospective studies can be mounted to answer 1) Assess the prevalence of gene variants in
numerous questions regarding the etiology of different populations.
birth defects and other reproductive outcomes 2) Assess the magnitude of disease risk asso-
with a focus on gene-environment interaction. ciated with gene variants in different
populations (relative and absolute risks).
HUMAN GENONE EPIDEMIOLOGY 3) Assess the contribution of gene variants to
NETWORK (HuGE Net) the occurrence of the disease in different
populations (attributable risks).
Because of the complexities of information 4) Assess the magnitude of disease risk
that will emerge from gene discoveries and the associated with gene-gene and
need for a systematic epidemiologic approach gene-environment interaction in different
to the evaluation of new genes and their vari- populations.
ants, the Centers for Disease Control and Pre- 5) Assess the validity of genetic tests in pre-
vention (CDC), with many partners, recently dicting disease risk in different popula-
launched a new collaborative initiative, the tions (positive and negative predictive val-
Human Genome Epidemiology Network ues).
(HuGE Net: Khoury and Dorman, ‘98). HuGE 6) Evaluate how frequently genetic tests and
Net represents the collaboration of individuals services are used in different populations
and organizations from diverse backgrounds and the determinants of their use.
who are committed to the development and dis- 7) Evaluate the impact of genetic tests and
GENETIC SUSCEPTIBILITY TO BIRTH DEFECTS 20
services on morbidity, disability, mortality Trends in infant mortality attributable to birth de-
and cost in different populations. fects--United States, 1980-1995. MMWR
HuGE Net will provide a coordinated global Collins FS, Patrinos A, Jordan E, Chakravarti A,
means of disseminating the epidemiologic in- Gesteland R, Walters L, and the members of the DOE
formation resulting from the Human Genome and NIH planning groups. 1998. New goals for the
Project. It will evolve as a collaboration among U.S. Human Genome Project: 1998-2003. Science
epidemiologists, geneticists, basic scientists, Oct 23: 682-689.
Hubbard R, Lewontin RC. Pitfalls of genetic testing.
and medical and public health practitioners 1996. N Engl J Med 334:1192-1194.
from governmental, professional, academic, Institute of Medicine. 1988. The future of public health.
industrial and consumer organizations world- Washington, DC: National Academy Press.
wide. Khoury MJ, Beaty TH. 1994. Applications of the
In the field of birth defects, there is a growing case-control method in genetic epidemiology. Epide-
miol Rev. 16:134-150.
need to conduct epidemiologic studies of ge- Khoury MJ. 1995. Commentary: contributions of epi-
netic susceptibility to birth defects as well as to demiology to the study of birth defects in humans.
disseminate the results of systematic epidemi- Teratology 52:186-189.
ologic reviews of the association between spe- Khoury MJ, Dorman JS. 1998. The Human Genome
Epidemiology Network (HuGE Net). Am J Epidemiol
cific gene variants and specific defects. Such a
public health assessment can be viewed as the National Birth Defects Surveillance Network
first crucial step in translating discoveries of (NBDPN). 1997. Congenital malformations surveil-
genes associated with birth defects into policies lance report. Teratology 56:1-175.
and interventions that reduce the risk for birth Online Mendelian Inheritance in Man (OMIM) (TM).
1998. Baltimore, MD:Center for Medical Genetics,
defects among susceptible populations. For fur-
Johns Hopkins University; Bethesda, MD: National
ther information on joining this global collabo- Center for Biotechnology Information, National Li-
rative effort, please consult the HuGE Net web brary of Medicine.
site at www.cdc.gov/genetics/huge.htm. Pagon RA, Covington M, Tarczy-Hornoch P. Helix: A
directory of medical genetics laboratories. 1998.
LITERATURE CITED http://www.hslib.washington.edu/helix/.
Posey DL, Khoury M J. Mulinare J, Adams MJ, Ou CY.
Centers for Disease Control and Prevention. 1997. 1996. Is mutated methylenetetrahydrafolate reductase
Translating advances in human genetics into public (MTHFR) a risk factor for neural tube defects? A
health action: A Strategic Plan. pooled analysis. Lancet 347:686-687.
Centers for Disease Control and Prevention. 1998.