American Journal of Medical Genetics Part C (Semin. Med. Genet.) 125C:1–3 (2004)

I N T R O D U C T I O N

Public Health Approach to Birth Defects,Developmental Disabilities, andGenetic Conditions

Interest in birth defects, developmental

disabilities, and genetic conditions by

public health professionals is relatively

recent. Birth defects were the first of

these groups of conditions for which a

major public health approach was used,

beginning in the early 1960s [Edmonds

et al., 1981], partially in response to the

epidemic of limb deficiencies that

occurred related to maternal thalido-

mide exposure [Lenz, 1988]. In addi-

tion, the recognition that, as infant

mortality declined, the contribution of

birth defects to infant mortality was

proportionally higher, led to an

increased interest among public health

professionals in this area. Because of

these factors, birth defects monitoring

(or surveillance) programs were set up

in the United States and several other

countries in the 1960s [Edmonds et al.,

1981; Oakley, 1985; Holtzman and

Khoury, 1986; Lowry et al., 1989].

While the initial focus was on birth

defects monitoring, investigators soon

recognized that monitoring programs

alone were unlikely to identify new

causes of birth defects, and thus research-

ers began to work on etiologic studies of

birth defects [Oakley, 1985]. Because

individual birth defects are rare, a more

efficient study design often used to

examine birth defects etiology is the

case-control study. In this type of study,

case infants with birth defects and

control infants without birth defects, or

alternatively, with birth defects other

than the birth defect of interest, are

identified from the same population, and

the prevalence of certain possible risk

factors for birth defects among case and

control infants is compared. Information

from case-control studies has led

researchers to a better understanding of

causes of birth defects. For example,

several case-control studies have shown

that mothers of babies with neural tube

defects were less likely to have taken

multivitamins during early pregnancy

than mothers of control infants [Rhoads

and Mills, 1984]. These results, taken

together with results from other studies,

including randomized, controlled trials

[Czeizel andDudas, 1992], subsequently

led to the U.S. Public Health Service

recommendation that allwomen capable

of becoming pregnant should consume

400 mg of folic acid per day to reduce

their risk of having a neural tube defect-

affected pregnancy [Centers for Disease

Control and Prevention, 1992].

Epidemiologic studies continue to

be a major source of information on

etiology of birth defects. It is important

that geneticists be familiar with epide-

miologic studymethodology so they can

effectively evaluate information from

these studies and use this information

to appropriately counsel patients. In

addition, the role of the geneticist is

increasingly being recognized in the

study of birth defects [Friedman, 1992;

Rasmussen et al., 2003]. The impor-

tance of accurate case definition and

classification of cases into presumably

homogeneous groups has been discussed

[Rasmussen et al., 2003], and ideally

these functions are performed by a

clinical geneticist or dysmorphologist.

Evidence suggests that most birth

defects are likely due to a combination of

genetic and environmental risk factors.

Many studies are now including studies

of genetic risk factors in their study

methodology [Beaty et al., 2001; Yoon

et al., 2001; Rasmussen et al., 2002;

Shawet al., 2002], again emphasizing the

need for geneticists to be familiar with

this methodology.

In this issue, the paper by Dolk

reviews the epidemiologic approach to

the evaluation of environmental causes

of birth defects. This paper reviews birth

defects monitoring, defines the broad

range of factors that are considered

environmental, and describes methods

for studying the contribution of these

factors to the causation of birth defects.

Dolk points out that an epidemiologic

approach is also useful in evaluating the

effectiveness of prevention programs

once risk factors have been identified.

Another paper in this issue byBotto et al.

reviews the evidence for a protective

effect of folic acid on birth defects other

than neural tube defects. In addition to a

reviewof previous studies, this paper also

discusses gaps in the evidence, recom-

mendations for future research studies,

and information helpful for counseling

families with a child with one of these

birth defects.

The public health interest in devel-

opmental disabilities is even more re-

cent. Although a concern regarding the

potential for environmental exposures

causing developmental disabilities was

raised in the 1950s with the discovery of

Sonja Rasmussen, MD, MS, and CynthiaMoore, MD, PhD, are both clinical geneticistsin the National Center on Birth Defects andDevelopmental Disabilities at the Centers forDisease Control and Prevention in Atlanta,GA. Dr. Rasmussen is currently the associatedirector for science for the Division of BirthDefects and Developmental Disabilities. Herresearch interests include epidemiology ofbirth defects and the natural history ofpediatric genetic conditions.

Dr. Moore is the team leader for thePediatrics Genetics Team. Her researchinterests include mechanisms of morphogen-esis, syndrome identification, birth defectssurveillance, and classification of birthdefects and genetic syndromes.

*Correspondence to: Sonja A. Rasmussen,1600 Clifton Road, CDC, MS E-86, Atlanta,GA 30333. E-mail: skr9@cdc.gov

DOI 10.1002/ajmg.c.30003

� 2004 Wiley-Liss, Inc.

an epidemic of mental retardation and

cerebral palsy related to maternal meth-

ylmercury exposure near Minamata Bay

in Japan [Gilani, 1975], developmental

disabilities monitoring programs in the

United States developed later than birth

defects surveillance programs. Monitor-

ing for developmental disabilities pre-

sents a number of issues, such as the

need for multiple ascertainment sources

(including some outside traditional

medical sources such as school systems),

the fact that most developmental dis-

abilities are not recognized at birth, and

the fact that developmental disabilities

are heterogeneous disorders [Yeargin-

Allsopp et al., 1992]. The first U.S.

population-based epidemiologic study

of developmental disabilities was per-

formed in metropolitan Atlanta during

the period from 1985 through 1987.

This study examined the prevalence of

each of four developmental disabilities

(mental retardation, cerebral palsy, hear-

ing impairment, and visual impairment)

among 10-year-old children [Yeargin-

Allsopp et al., 1992]. This study design

has been expanded to examine other

developmental disabilities, including

autism [Yeargin-Allsopp et al., 2003]. A

paper by Rice et al. in this issue discusses

their experience with monitoring of

developmental disabilities, particularly

autism spectrum disorders. This paper

discusses the public health role of moni-

toring these conditions, as well as the

many challenges. The next step in the

epidemiologic study of these conditions

is conducting etiologic studies that will

hopefully lead to a better understanding

of their causes. A multisite epidemio-

logic study of autism spectrum dis-

orders, to be conducted by the Centers

of Excellence for Autism and De-

velopmental Disabilities Research and

Epidemiology (CADDRE) (http://

www.cdc.gov/ncbddd/dd/aic/states/

#caddre), funded by the Centers for

Disease Control and Prevention, is cur-

rently in the planning stages. It is likely

that an approach similar to that used for

the study of birth defects, addressing

possible genetic and environmental fac-

tors, will be useful in addressing the

many questions about etiology. The

geneticists’ contribution to these studies

will be important because genetics

appears to play a major role in the

etiology of some developmental disabil-

ities and several developmental disabil-

ities, are associated with chromosome

abnormalities and single-gene condi-

tions [Shevell et al., 2003; Veenstra-

Vanderweele et al., 2003].

A paper in this issue by Dent et al.

addresses the etiology of another devel-

opmental disability—hearing loss. The

recognition that early diagnosis and

intervention in infants with hearing

loss results in improved outcomes has

led to the development of statewide early

hearing detection and intervention

(EHDI) programs throughout the Uni-

ted States [Joint Committee on Infant

Hearing, 2000]. This article describes a

project that identifies infants with hear-

ing loss using a state EHDI program.

This project uses a population-based

methodology and focuses on under-

standing the genetic and environmental

factors involved in the etiology of early

hearing loss. Another important goal of

this project is to develop a model

infrastructure for the linkage of genetic

services to state EHDI programs.

Although public health’s entrance

into the study of genetic disorders has

generally been later than that for birth

defects or developmental disabilities, it is

important to recognize that public

health has long had a role in genetics

through state newborn screening pro-

grams throughout the United States.

Newborn screening in the United States

began in the early 1960s with the

development of a newborn screening

test for the identification of phenyl-

ketonuria [Guthrie and Susi, 1963].

Since that time, many changes in new-

born screening have occurred, including

expansion to all states and to a number of

additional disorders. The paper by

Comeau et al. discusses the experience

of the New England Newborn Screen-

ing Program with a recent expansion

of services, adding disorders identified

by tandem mass spectrometry (e.g.,

medium-chain acyl-CoA dehydrogen-

ase deficiency) and by a combination of

protein and DNA analyses (e.g., cystic

fibrosis). Because additional disorders

are likely to continue to be added to

newborn screening programs, a review

of lessons learned regarding challenges to

the medical community (such as the

number of contacts and types of services

required) is extremely valuable.

Public health involvement in many

other single-gene disorders has been

complicated by their low prevalence,

making population-based surveillance

systems, such as those used for birth

defects and developmental disabilities

monitoring, difficult. Because of this,

other methods have been designed to

study these conditions. One such

method is discussed in the paper by

Birch and Friedman. In the paper they

discuss the development of a genetic

disease-specific clinical database, the

National Neurofibromatosis Founda-

tion International Database. Their arti-

cle reviews the strengths and limitations

of this methodology, summarizes studies

performed using this database, and

provides a list of recommendations re-

garding the operation of such a database.

The experience of Birch and Friedman

will be useful to investigators who wish

to develop clinical databases for other

genetic conditions.

Adult-onset disorders often have a

genetic component, but in most cases

the genetic factors involved are not well

understood. In this issue, Scheuner et al.

summarize information on Mendelian

conditions that feature common adult-

onset disorders. This article provides a

list of these Mendelian conditions and

summarizes genetic testing and guide-

lines for management and prevention,

where available. Information in this

article will provide additional support

for the use of family history, recently

advanced as an important tool for public

health and preventive medicine [Yoon

et al., 2002, 2003]. In addition to clues

to possible single-gene disorders, col-

lection of a family history can provide

information about the presence of

shared genes, shared environments, and

complex gene-environment interac-

tions [Khoury, 2003]. It has been

suggested that family history can provide

a bridge [Khoury, 2003; Yoon et al.,

2003] between genetics (defined as ‘‘the

study of single genes and their effects’’)

and genomics (defined as ‘‘the study not

2 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) INTRODUCTION

just of single genes, but of the functions

and interactions of all the genes in the

genome’’) [Guttmacher and Collins,

2002]. Public health approaches will

need to adapt to meet new challenges

so that the application of genomics to a

broad range of human diseases can

become a reality [Khoury, 2003].

Despite the importance of birth

defects, developmental disabilities, and

genetic conditions to the public’s health,

and thus the importance of their study,

several issues need to be taken into

consideration. One issue is that of con-

fidentiality of information collected on

patients as part of studies. Although the

recent adoption of the Health Insurance

Portability and Accountability Act of

1996 (HIPAA) allows for collection of

public health information [Centers for

Disease Control and Prevention, 2003],

this act provides new challenges. Ethical,

legal, and social issues [Clayton, 2003] all

have been raised in response to the plan

to include public health evaluation of

these conditions. The paper by Hodge

discusses the difficulties in balancing

potential public health benefits of gene-

tic testing and screening with possible

risks to individuals and populations.

Despite these issues, the important

information that can be gleaned from

public health examination of these con-

ditions should not be underestimated.

Insight provided by clinical and mole-

cular geneticists and dysmorphologists is

valuable to epidemiologic studies of

these conditions. A partnership between

professionals with expertise in epide-

miology and public health and those

with expertise in clinical and molecular

genetics and dysmorphology will be

crucial to the future success of these

studies.

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Sonja A. Rasmussen*

Cynthia A. Moore

Guest Editors

INTRODUCTION AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 3