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When should the possibility of a genetic disorder cross your radar screen?
Publish date: May 1, 2004By:

Benjamin Siegel, MD, Jeff Milunsky, MD
Source: Contemporary Pediatrics
The role of the generalist pediatrician in the specialized field of genetics is key: Screen children for genetic disorders; recognize when assessment findings point to a genetic disorder and warrant referral to a geneticist; and counsel families about an issue with potentially far-reaching implications.
It was in a pub, of all places, in Cambridge, England, that Drs. Francis Crick and James D. Watson announced they had discovered the double helical chemical structure of DNA and had described the DNA nucleotides.1 The date was February 28, 1953. Just a month before, Rosalind Franklin, PhD, had processed an X-ray photograph of the helical structure of DNA, which she shared with Watson.
Medical science has come a long way in half a century. The Human Genome Project was completed in 2001 by a large public collaborative and private initiative.2,3 Technologies that allow us to understand and diagnose diseases and disease processes are increasingly available. These include routine chromosome analysis revealing structural and numeric anomalies (Down, Klinefelter, and Turner syndromes), fluorescent in situ hybridization (FISH) uncovering gene deletion/duplication syndromes, DNA analysis using polymerase chain reaction (fragile X),4 and, more recently, microarray analysis of a large number of genes (10,000!). These technologies allow a search for candidate genes for certain diseases, enable predictions about prognosis, and delineate whether a specific disease subtype might respond to certain medications.
Despite the huge assist from technology in the field of genetics, challenges for the primary care provider—the generalist pediatrician—remain. Chief among them is recognizing which patients are likely to have a genetic disorder and should be tested and referred. In this review, we outline a systematic approach for gathering data that point to a possible genetic disease or to a predisposition to a genetic process that carries a significant diagnosis and prognosis. Specifically, we highlight that aspect of the initial assessment of the patient that should make you think "genetic disorder." We also review the ethical, psychosocial, and legal implications of a possible genetic diagnosis. And, we discuss the benefits of collaborating with a clinical geneticist.
To highlight the many facets of genetics in actual practice, we begin with a case example.

Looking beneath a problem of language delay
You are seeing a 30-month-old boy in your office for the first time. His mother is worried that his language is not developing at the same pace that it developed in her other children. She reports that her previous pediatrician suggested that the parents wait a while to see how he develops. The boy says "mama" and "dada" and a few other words, and he can point to parts of his body when asked. He relates well to his parents and siblings and has no unusual stereotypical behaviors. He responds to sound and appears to hear well; he passed the newborn hearing screen.
The boy is the youngest of three children; his two older sisters are developmentally normal and, by a quick screen, very bright. His parents are both professionals. His birth history is noncontributory and the pregnancy was uneventful. He is a picky eater but all the food he eats is of good quality. There is no reason to suspect child abuse or neglect. Mom has described how both parents have read to their youngest son and nurtured his growth and development just as they did with his sisters.
The physical exam is notable for slight hypotonia and a head circumference at the 75th percentile, height at the 35th percentile, and weight at the 5th percentile. There are no significant dysmorphic features. You review the medical record brought by the family and note that weight, height, and head circumference have been tracking along those percentiles since 3 months of age. You're struck by the discrepancy in anthropometrics. You're thinking about hearing loss, mental retardation, pervasive developmental delay or Asperger syndrome (a developmental language disorder), and, of course, a genetic problem.
You gather specific information from the mother about her family. She comes from a large one; one brother has a significant learning disability and another has a psychiatric problem. You note that the mother has no obvious abnormal physical findings. Putting together data from the developmental history, physical exam, and family history—notably, two maternal uncles with a cognitive or psychiatric problem—you believe the probability of a genetic problem in the patient is high.
Because no clinical geneticists practice in your community, you search several Web sites on genetic issues and resources. One site helps you identify a clinical geneticist at a medical center 100 miles from your office, and you call him for consultation. He agrees that this patient may have a genetic problem and suggests ordering a chromosome analysis and a DNA test for fragile X syndrome. Before ordering these tests, you discuss with the parents ethical, legal, and psychosocial issues pertaining to genetic testing and how the test results could affect their child and entire family. Mother has told you that she wants to have at least one more child.
The testing is done, and the findings are positive for fragile X syndrome. You meet with both parents to share the news and begin the process of discussing options for the child's development, the parents' feelings, and preliminary counseling. You recommend that the family consult with the clinical geneticist with whom you spoke. You explain that a clinical geneticist, or a genetic counselor supervised by a geneticist, has a detailed understanding of the spectrum of genetic issues, including reproductive counseling; knows the specific tests available; and can meet with parents to discuss the ethical, legal, and psychosocial issues. The clinical geneticist can also maintain contact with the family and provide them with the latest information about genetic testing, prognosis, and treatments.
The parents are grateful to you for making the diagnosis. They also appreciate your referral to the clinical geneticist. You let them know that, as their pediatrician, you will work with them as they face what is likely to be a long journey with many challenges.
* * * * * *
With all new patients, pediatricians identify pertinent screening history and physical examination data to detect health and psychosocial risks. In the sections that follow, we focus on those aspects of the initial assessment that should make you consider a possible genetic disorder. There are five key areas of inquiry for a genetic focus: pregnancy history, neonatal history, patient history, family history, and physical examination.

Pregnancy history
Many variables in the pregnancy history are relevant to identifying a possible genetic disorder (Table 1). The older the mother (especially if she was 35 or older at delivery), the greater the risk of the baby being born with a numeric chromosome abnormality such as Down syndrome. A history of repeated premature births also predisposes to a genetic problem. Keep in mind, too, that a multiple birth increases the risk of a congenital anomaly, which may have a genetic basis. So does a breech delivery or a family history of congenital hip dysplasia.
Noteworthy aspects of the pregnancy history
Age of mother
History of repeated prematurity
Position of the fetus
Results of fetal ultrasonography
Amniotic fluid (oligohydramnios or polyhydramnios)
Blood screening tests
Multiple births
Medications and known teratogens
Decreased fetal movement
Results of the fetal ultrasonographic examination may provide information about certain chromosomal disorders as well as significant information about other conditions that may be genetic in origin, such as heart, kidney, and gastrointestinal tract problems; neurologic disorders; and limb and skeletal disorders. Amniotic fluid abnormalities, both polyhydramnios and oligohydramnios, may suggest GI and renal anomalies. Maternal blood screening tests inform you about possible hemoglobinopathies, open neural tube or ventral wall defects, and chromosomal disorders (the triple/quadruple screen).5,6 One always worries that maternal medication such as hydantoin and other known teratogens such as alcohol could have caused chromosomal damage. Decreased fetal movements suggest possible neurologic problems that may have a genetic etiology.

Neonatal history
As with a pregnancy history, a focused neonatal history (Table 2) can point to a genetic problem. Symmetric intrauterine growth restriction (IUGR) suggests an event occurring during the first trimester or that is genetic in origin. Most IUGR infants are low weight for gestational age, with sparing of the height and head circumference. Infants who are born large for gestational age without a specific reason may also have a genetic disorder.
Noteworthy areas in the neonatal history
Symmetric intrauterine growth restriction
Large for gestational age without a reason
Hearing loss
Persistent hyperbilirubinemia
Poor adaptation to the environment
Hypotonia or hypertonia
Remarkable metabolic screen results
With the advent of the neonatal hearing screen, hearing-impaired infants are being identified earlier than in the past. At least 50% of cases of deafness have a genetic basis.
Persistent hyperbilirubinemia, both direct and indirect, may be associated with an inherited metabolic disorder—galactosemia and tyrosinemia, for example. Poor adaptation to the environment, including temperature and heart rate instability, as well as poor feeding may be initial clues to a genetic disorder.
Hypotonia or hypertonia without evidence of a complicated delivery or IUGR may point to cerebral palsy, which often has a genetic component. Hypotonia may, in fact, be a sign of any of a number of genetic disorders, including Down syndrome and Prader-Willi syndrome, as well as of a congenital myopathy or neuropathy such as spinal muscular atrophy.
Neonatal seizures may indicate a neurologic problem or a complex metabolic problem (hypoglycemia, hypocalcemia, hypomagnesemia, aminoacidurias, etc.) with a genetic cause. In many states, the newborn metabolic screen tests for an expanded number of disorders, most of which are genetic.

Patient history
Later in infancy or childhood, the presence of developmental delay, recurrent seizures, hypotonia or hypertonia, or failure to thrive without an obvious cause (Table 3) should make you think of a possible genetic disorder warranting investigation or referral. (Testing conducted as part of a medical evaluation is discussed in the section "The physical exam.")
Noteworthy areas in the patient's history
Developmental delay
Recurrent seizures
Hypotonia or hypertonia
Failure to thrive
Family history
The family history, critical in identifying the patient's risk of a genetic disorder, should cover three generations and list the known influences of genetics on the patient's health (Table 4).
Important areas in the family history
Major congenital anomalies
Mental retardation
Known genetic diseases
Metabolic disorders
Chronic serious illnesses
Heart disease (conduction problems, structural problems, first-degree relative <55>It is helpful to create a comprehensive family tree to keep in the medical record (see the figure on constructing a family pedigree).7 The likelihood of a genetic disorder in the patient is increased if there is a positive three-generational family history.
PLEASE NOTE: If you are using Internet Explorer version 6 or higher, after clicking to enlarge the graphic, click the picture icon that appears in the lower right-hand corner of the graphic.
The history should be approached in a sensitive way. Tell the family members and the patient (if he or she is old enough to understand) that you will be asking questions to assess potential genetic risk and that ethical, psychosocial, and legal considerations will be discussed before any testing takes place.
If the family has a history of heart disease, the pediatrician should be particularly concerned about a possible genetic disorder when that history includes conduction problems, structural problems, or any first-degree relatives younger than 55 years with hypercholesterolemia, stroke, angina, or a history of myocardial infarction. Similarly, with cancer, the major concerns are those cancers that are genetically linked: breast, GI, and retinoblastoma. Many renal and neurologic diseases that have a genetic component are important to identify because of risks to the patient. Examples include polycystic kidney disease and Huntington's chorea. A family history of multiple miscarriages, stillbirths, significant learning disabilities, and familial psychiatric problems add to the risk analysis.
For completeness, find out the parents' ethnicity and whether they have a shared ancestry to help uncover heritable diseases. There is a higher carrier frequency of Tay-Sachs, for example, in Ashkenazi Jewish and French-Canadian families. Consanguinity is an additional risk factor, especially for an autosomal recessive genetic disorder, and should be documented.

The physical exam
Minor congenital anomalies (Table 5) are ubiquitous and a diagnostic challenge.
Some minor congenital anomalies
Cranium and scalp
Triple hair whorl,Patent metopic suture Flat occiput Prominent occiput Frontal bossing Widow’s peak EarsLack of helical folding (singlehelix: flat without ridges orindentations) Ear lobe crease Ear lobe notched Lop ear (forward displacedand protruding) Cup-shaped ear Thickened helixHelix attached to scalp SinusesBranchial Preauricular Ear lobe Helical Pilonidal
Face and neck
SynophrysFlat bridge nose Hypotelorism Hypertelorism Nostrils anteverted Epicanthal foldIris freckles Upward palpebral slant Downward palpebral slant Short palpebral fissures Cleft uvula Long philtrum Short philtrum Smooth philtrum Microstomia Macrostomia Macroglossia Micrognathia Webbed neck Redundant neck skin Ptosis
Extra nipples Single umbilical artery Umbilical herniaDiastasis rectus Glandular hypospadias Shawl scrotum (redundantskin folds over the base and the top of the penis) Vaginal tag
Cubitus valgus Tapered fingers Overlapping fingers Broad thumb, broad great toe
Clinodactyly Nails hyperconvex orhypoplastic Increased space betweentoes Syndactyly, toes 2-3 Overlapping digits
Adapted from Stevenson RE, Hall JG, Goodman RM: Human malformations and related anomalies, in Oxford Monographs on Medical Genetics, No. 27, New York, Oxford University Press, 1993
When three or more minor anomalies are present, there is an approximate 20% risk of a major anomaly or mental retardation.8 And it should take only one major anomaly (Table 6) to think "genetics." A general principle of the screening physical exam is that, when one anomaly is present, you should search carefully for others. A diagnostic workup is recommended in patients with either three or more minor anomalies, selected major anomalies, a combination of major and minor anomalies, or a recognized pattern or distribution of anomalies.
Examples of major congenital anomalies
Cleft lip, cleft palate
Congenital heart disease
Brain anomalies, neural tube defects
Specific skin lesions
Generalized dysmorphism and growth restriction
Asymmetry (facial, skeletal, limb)
Multiple minor congenital anomalies (see Table 5)
If the patient has congenital heart disease (a significant ventricular septal defect [VSD], other structural heart disease, or a complicated dysrhythmia) with a strong family history, consider a genetic cause. About 3% of all congenital heart disease is caused by a single mutant gene—autosomal dominant, recessive, or X-linked; an example is Noonan syndrome with pulmonic stenosis or hypertrophic cardiomyopathy. In addition, about 5% of congenital heart defects are caused by major chromosomal abnormalities such as Turner (XO) and Down syndrome (trisomy 21). Chromosome 22q11 microdeletions are found not only in DiGeorge and velocardiofacial syndromes, but also in "isolated" conotruncal heart defects, VSD, and tetralogy of Fallot. A family history of hypercholesterolemia or heart attacks in younger adult relatives should prompt you to perform cholesterol screening in the patient at 2 years of age.
Significant brain malformations and neural tube defects suggest a genetic cause or an environmental influence.
About 50% of newborns with an omphalocele have additional congenital anomalies, and 20% to 35% of these anomalies are associated with major chromosomal abnormalities.9
Specific skin pigmentary changes, such as café-au-lait macules, hypopigmented macules or streaks, and cutaneous hemangiomas, suggest a genetic disorder with possible CNS consequences. Also consider a genetic process if there is generalized dysmorphism with or without abnormal anthropometrics or asymmetry (facial, skeletal, and limb). With hepatosplenomegaly, consider lysosomal storage diseases (lipid disorders, mucopolysaccharidoses, and disorders of glycoprotein synthesis), especially if there is a metabolic problem or failure to thrive with progressive deterioration.
Keep in mind that metabolic disorders have protean manifestations. The neonatal presentation may include feeding problems, lethargy, seizures, altered tone, tachypnea, coma, and a "septic" appearance. Biochemical disturbances may include hypoglycemia, metabolic acidosis, and hyperammonemia. Liver disease, myopathy, and cardiomyopathy may be an early or late manifestation of a metabolic syndrome.
A progressive neurodegenerative course, hepatosplenomegaly, somatic dysmorphism, skeletal dysplasia, and ophthalmologic findings may suggest a storage disease. Neurologic findings that may suggest a metabolic disorder include ataxia, developmental delay, and exercise intolerance.
For the acute presentation of a suspected metabolic disorder, a number of laboratory tests may be useful: electrolytes, BUN, glucose, blood gas analysis, liver function tests, ammonia, lactate, pyruvate, and urine analysis. Further testing may include uric acid, triglycerides, cholesterol, creatine phosphokinase, carnitine, and amino and organic acids. If a storage disease is being considered, a skeletal survey may be indicated.
If clinical findings or results of tests ordered as part of a medical evaluation do not show a cause for a problem detected on history or physical exam (e.g., developmental delay, recurrent seizures, hypotonia or hypertonia, failure to thrive), consider referral to a geneticist. In the child with a developmental disability of unknown cause, first order a chromosome analysis and DNA test for fragile X syndrome (the most common inherited genetic disorder causing mental retardation), regardless of whether the patient has associated dysmorphism or a family history of developmental disability.10 If results of these two genetic tests do not reveal a diagnosis, or if they do and the expertise of a specialist is desired, refer to a clinical geneticist. Further evaluation that includes FISH testing for specific microdeletion/duplication disorders, as well as subtelomeric FISH studies, may now be indicated for your patient.
In general, if you suspect that your patient has a genetic disorder and are unsure which tests would be useful, refer to a clinical geneticist. When deciding whether to refer to a geneticist, consider, too, whether you have enough specialized knowledge to know both when to order a particular test and how to interpret the results.

Ethical considerations
Genetic information has the power to help or harm patients and family members, including those outside the nuclear family. That power must be taken into account when working with the family. A genetic diagnosis can have significant, even life-threatening, ramifications for the health of the patient—as when the mother is a carrier of a BRCA1 gene mutation for breast cancer or there is a family history of Huntington disease.
Ethical issues should be considered from the start—not later, as an afterthought. Review all relevant ethical issues before genetic testing to ensure that the parents and child are aware of the actual and potential consequences of their decisions.
One of the most important principles in medical ethics is autonomy. The family should be told that they will decide what is appropriate, within practice guidelines. You, as the child's pediatrician, will help them in the decision-making process, which is based upon the health risks and benefits and the family's goals, values, and religious, spiritual, or cultural perspective.
The principles of beneficence and nonmaleficence also come into play. Obviously, health-care providers want to do "good," but what happens when the good produces an unintended, harmful consequence? Let us assume that, in the clinical case presented earlier, the mother was adopted as an infant and that this fact was a source of pain to her for many years. Revisiting the fact that she is adopted may resurrect that pain. Now that she knows she is a carrier of fragile X, she may feel a moral imperative to discover if others in her biologic family are carriers. This would mean finding a lawyer and breaking into what is probably sealed information. This course of action may further reopen psychological wounds and could well have an impact on the lives of others.
The final general ethical principle is justice. To what degree are people with genetic problems treated unequally in our society? Because of their genetic diagnosis or predisposition, are they able to get health insurance or work? How well does our medical care system and society distribute goods and services to meet the needs of its citizens with a genetic disease, especially if it is associated with a significant disability?11
The principles of informed consent and confidentiality are relevant, too; these are, of course, legal as well as ethical tenets. Parents may not wish to share the genetic information with other family members even though it may have health implications for them. Pediatricians should protect the confidentiality of test findings to the extent permissible by law. 12 (A clinical geneticist has a responsibility to document his or her recommendations about sharing information with relevant family members. If you choose not to consult with a clinical geneticist, this responsibility may fall on you.) In clinical genetic counseling, the approach is one of nondirective counseling within a collaborative relationship. Your role is to help the family weigh all the risks and benefits of decisions that affect them and their family members, and to be honest about the uncertainties, especially about prognosis.
Many families believe that, if testing cannot change anything, it should not be done. Conversely, there are times when a family would like to have a child tested but it may not be in the child's best interests, and the pediatrician may decide not to comply with the parents' wishes. For example, if there is a significant genetic predisposition with a high likelihood of affecting the child (Huntington disease or a BRCA1 gene mutation) the American Academy of Pediatrics Committee on Bioethics recommends that testing be deferred until the patient reaches an age of consent and can weigh the risks and benefits himself, rather than performing presymptomatic genetic testing when the child is preadolescent to satisfy parental needs.12–17

Psychosocial issues
Genetic testing and genetic disease are complex topics often not easily understood by family members. Strong emotions frequently limit rational problem solving. Responses to learning of a genetic condition include guilt (including the feeling by some parents that they have "caused" the disease in their child), anger, denial, shame, humiliation, and sadness. Many psychosocial issues are involved (Table 7) and it is important for you to be aware of them.
Psychosocial issues related to a genetic diagnosis
Emotional response to the news (guilt, sorrow, loss of hope for a "normal" child)
Feelings of stigmatization and marginalization
Fear of discrimination
Family implications; impact on family and work relationships
Revelation of nonpaternity
Implications for reproductive choices
Community and culture
Diminished access to medical services
Relationship to the medical community (teamwork or comprehensive fragmentation)
Stigmatization, marginalization, and discrimination—socially, in the workplace, and in school—and diminished access to insurance are significant concerns of patients and family members. Life, health, and disability insurance may not be attainable or may be prohibitively expensive for those people who have, or are predisposed to, a genetic disease.
The implications for the entire family can be significant. As with many families of children who have a serious medical condition with no genetic basis, many families of children who have a genetic disorder have to work very hard to manage all of the appointments and services for those children. This affects other children in the family, parental relationships with extended family, and parents' work life. Sometimes, data on genetic testing reveals that the father of the baby is, unbeknownst to him, not the biologic father. It may be especially poignant when the mother reveals to you, confidentially, that the child's father is someone other than her current partner and she does not want you to share this information. This is a psychosocially and ethically challenging aspect of genetic counseling, and there may be no easy answer.4 Collaboration with a clinical geneticist may be helpful.
When counseling families, be aware of issues related to the family's community and culture, including the possibility that the family does not consider the genetic condition under discussion to be a disease. For example, many people with deafness do not believe it is a disease but merely a difference in ability to communicate. Through signing, they communicate just fine. These parents may not wish their child to have a cochlear implant.
Last, consider the family's relationship to the medical community. Patients with genetic disorders require many health professionals to provide comprehensive care. This necessitates excellent teamwork, including clear communication among team members. You are in an excellent position to coordinate these services and prevent fragmentation of care—and parents want you to do so.

Legal protections
Identifying a genetic disorder may lead to diagnosis of a developmental disability or another condition that is covered by federal and state legislation. Review legal protections with the family and advocate for them in gaining access to programs that provide special services to disabled people, including early intervention programs mandated by the Individuals with Disabilities Education Act. [Editor's note: For more on educational opportunities for children with disabilities, see "
Educating children with disabilities: How pediatricians can help " in the September 2002 issue.] The family may also be eligible for federal supplemental security income (SSI) disability benefits.
Some insurance programs provide respite care to families, particularly when a child has significant health and nursing care needs. Even something as simple as advising parents to apply for a "handicapped parking" plaque for their vehicle can be advantageous when a child is older and requires a wheelchair or other form of transportation.
The Family Medical Leave Act (FMLA) can be helpful, but it is limited. The act allows for three months of leave in a 12-month period without loss of job, but it does not require continued payment of salary during this time. It also applies only to employers with 50 or more employees, and, although parents of children who are hospitalized are eligible to take leave for that reason under the FMLA, parents whose children require ambulatory visits to multiple clinicians are not.
Various laws ensure rights for the disabled, prohibit discrimination (e.g., the Americans with Disabilities Act), provide privacy protections, and protect freedom of choice. To maintain patients' ability to exercise freedom of choice, it is important to keep up to date on genetic information so that you can advise families on the availability of new tests and approaches to genetic diagnoses (the box "
Helpful Web sites on genetic disorders " below lists helpful Web sites).
Keeping abreast of new technologies and advances in genetics, as well as making referrals to, and having consultations with, a geneticist, will also help limit your liability under the "loss of chance" doctrine. This doctrine states that failure to make a diagnosis (when such failure falls below the standard of care), not sharing information when there is a known risk to the pregnant woman or the family, or not performing standard screening tests correctly and when appropriate deprives the parents of their right to make informed reproductive choices.

Partnering with a geneticist
In the best of all possible worlds, the primary care provider collaborates with a colleague who is a clinical pediatric geneticist. We recommend referring to a clinical geneticist any patient that you suspect has a genetic problem based on history or physical exam findings, particularly those with a developmental disability of unknown etiology. You may decide to refer immediately, without ordering any genetic tests, or after ordering a chromosome analysis and DNA test for fragile X, when such tests are indicated.
When you refer to a geneticist, let the family know what to expect. Tell them that the consultation will include intense data gathering and a comprehensive physical examination, and it may require a variety of genetic studies that may involve testing of immediate and extended family members. Request that they bring pictures of family members to the geneticist. Inform the family that, as part of your request for consultation, you will be asking the geneticist certain questions; review these questions with family members, as well as the specific medical information that you will be sharing with the geneticist. You should supply the geneticist with relevant data (growth charts, etc.) and the specific questions(s) you would like answered.
Address pertinent ethical, psychosocial, and legal issues before the referral. Inform the family that they will be in a position to choose a course of action that seems appropriate to them. Tell them that you will follow up with them after the genetics consultation.
Developing a good working relationship with the genetics consultant will help accomplish the goals of care. Be clear with the geneticist about your respective roles. If a clinical geneticist is not available where you practice, you can locate one through one of the
Web sites listed below. If consultation with a clinical geneticist is not feasible, the pediatrician should order a chromosome analysis and a fragile X DNA test for a child with developmental delay and refer to a pediatric neurologist or a developmental pediatrician.
The brave new world of genetics
Most diseases have a genetic component, yet relatively few require you to begin the process of identifying a possible genetic diagnosis and counseling the family about what will happen as the process moves forward. This anticipatory guidance sets the stage for effective genetic counseling.
Once you start the process, you should, ideally, consult and collaborate with a clinical geneticist or a genetic counselor under the supervision of the geneticist. Now that the sequence of the human genome has been determined and rapid discoveries are being made in the field of genetics at the diagnostic and therapeutic levels, greater collaboration between the general pediatrician and the clinical geneticist is called for. This teamwork will provide the most effective and up-to-date approaches to the diagnosis and management of genetic disorders from biologic, ethical, legal, and psychosocial perspectives.
1. Crick F, Watson JD: Molecular structure of nucleic acid. Nature 1953;191:737
2. Venter JC: The sequence of the human genome. Science 2001;291:1304
3. Lander ES, Linton LM, Collins FS, et al: Initial sequencing and analysis of the human genome International Human Genome Sequencing Consortium. Nature 2001;409:860
4. American Academy of Pediatrics: Molecular genetic testing in pediatric practice. A subject review. Pediatrics 2000;106:1494
5. Wald NJ, Huttly WJ, Hackshaw AK: Antenatal screening for Down's syndrome with the quadruple test. Lancet 2003;361:835
6. Mennuti MT, Driscoll DA: Screening for Down's syndrome–too many choices. N Engl J Med 2003;349:1471