Medical Genetics

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Public health and medical genetics are strongly linked. The applications of both begin at preconception, when folic acid supplementation can be used to reduce birth defects, and continue through pregnancy, when testing is often done to detect abnormalities. At birth, screening of newborns for biochemical disorders enables the prevention of morbidity associated with diseases such as phenyl-ketonuria. The use of genetic screening for disorders expressed at older ages is expanding as a result of advances in molecular biology and cancer monitoring. With knowledge of the human genetic code, there will be acceleration in the diagnosis and treatment of genetic conditions and, consequently, the need for its incorporation into public health.


The types of genetic disorders that may occur in any population can be classified into five categories:

  1. Chromosome disorders are caused by the loss, gain, or abnormal arrangement of one or more chromosomes. Their frequency in the population is about 0.2 percent. Examples include Down syndrome and Turner's syndrome.
  2. Mendelian disorders come from the mutation of a single gene. The transmission pattern is divided further into autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. The frequency is about 0.35 percent.
  3. Multifactorial disorders involve interactions between genes and environmental factors. The nature of these interactions is poorly understood. The risks of transmission can be estimated empirically, and the estimated frequency in the population is about 5 percent. Examples include cleft lip and neural tube defects.
  4. Somatic genetic disorders are not inherited but occur after conception. They often give rise to malignancies and involve environmental and genetic influences.
  5. Mitochondrial disorders arise from mutations in the genetic material in mitochondria. Mitochondrial DNA is transmitted only through the maternal line. These conditions are rare.


Down Syndrome. The most frequent chromosome disorder (1 in 800 births in the United States) is the one associated with Down syndrome (also called Down's syndrome or trisomy 21). A common cause of mental retardation, Down syndrome is caused, in most instances, by an extra chromosome being segregated in an egg during development. The event is random. Another cause (3 to 4% of cases) is a robertsonian translocation, in which chromosome 21 attaches to another chromosome. In this case, although the amount of genetic material is normal, the number of chromosomes is 45 instead of 46. The offspring of a parent with a robertsonian translocation have a 25 percent chance of having Down syndrome. Accordingly, karyotyping (the examination of chromosomes) is required for all children born with Down syndrome.

Down syndrome can be diagnosed during the prenatal period with amniocentesis and chorionic villous sampling. These tests involve obtaining either amniotic fluid or a sample from the placenta. Risks for Down syndrome increase with robertsonian translocation and previous birth of a child with Down syndrome; increasing maternal age; and low serum levels of maternal alpha ([.alpha])-fetoprotein (because the liver of a fetus with Down syndrome is immature, [.alpha]-fetoprotein levels are lower than normal). Further risk for Down syndrome can be ascertained by measuring the serum levels of [.alpha]-fetoprotein, estrogen, and human chorionic gonadotropin (hCG) in the blood.

Turner's Syndrome. Turner's syndrome is a disorder of growth and development occurring in about 1 in 2,000 births. The syndrome involves errors in one of the X chromosomes and is often associated with heart defects, osteoporosis, infertility, and short stature. Diabetes, hypothyroidism, and congenital urinary-tract abnormalities are also more common among patients with Turner's syndrome (35 to 70%) than in the general population. Edema before birth may cause webbing of the neck, a low posterior hairline, and ear abnormalities.

Klinefelter's Syndrome. Klinefelter's syndrome, characterized by a 47, XXY karyotype, is a disorder of growth and development, occurring in about 1.7 per 1,000 male infants. The disorder usually is diagnosed at puberty or during an infertility evaluation. In adolescents, its characteristics include gynecomastia (40%), small testicles, tall stature, and an arm span that is greater than the person's height. Klinefelter's syndrome is the most common cause of hypogonadism in males, and testosterone levels are about half the normal value, while follicle-stimulating hormone and lactate dehydrogenase levels are increased. Treatment includes testosterone, and occasionally mastectomy for gynecomastia.


Dominant Disorders. With classic dominant inheritance, an affected person has a parent with the same disorder. The parent usually mates with someone who does not have the genetic disorder, and the offspring have a 50 percent chance of having the disorder. Typically, predisposition for the disorder is carried on one chromosome, and expression of the disorder is modified by the chromosome makeup of the other parent. The dominant condition usually does not alter the ability to reproduce but tends to alter proteins that provide structure to a body. Examples of dominant disorders include Marfan syndrome (this has changes in the materials that give tissues strength), Huntington's disease (a degenerative nerve disease), neurofibromatosis (a disease that changes nerve structure), achondroplasia (a condition that alters cartilage), and familial hypercholesterolemia (a condition causing atherosclerosis because of increased cholesterol level). About 6 percent of cases of breast cancer are inherited dominantly.

Recessive Disorders. With classic recessive disorder inheritance, both mates have a gene for the disorder. The offspring have a 25 percent chance of having a normal gene pattern, a 50 percent chance of being a carrier, and a 25 percent chance of having the disorder. Carriers tend to have a reproductive advantage in certain environments; for example, sickle cell trait carriers are more resistant to falciparum malaria than noncarriers. The disorders tend to involve enzymes, and if siblings have the disorder it tends to be of the same severity because there is no modifying gene, as in a dominant disorder. If untreated, recessive disorders tend to cause death at an early age.

Certain nationalities are associated with recessive disorders. For example, people of Caribbean, Latin American, Mediterranean, or African descent have higher rates of sickle cell anemia or thalassemia, and those of Ashkenazi Jewish origin have higher rates of Tay-Sachs diseaseand possibly Gaucher's disease (1 in 450 births). Screening is important for each of these groups.

In addition to the medical history, laboratory screening tests performed on newborns can detect recessive disorders. States require that many of these tests be performed. Examples are phenylketonuria, galactosemia, and hemoglobinopathy tests. The ideal time for conducting these laboratory studies is seventy-two hours after birth, although with early hospital dismissal of newborns, this timing is difficult. The American Academy of Pediatrics recommends that screening tests be performed in all infants before dismissal from the hospital. If the infant is dismissed less than twenty-four hours after birth, the screening tests should be repeated before the infant is two weeks old. Many medical clinics recommend rescreening if dismissal occurs at forty-eight hours, as the diagnoses of phenylketonuria and hypothyroidism may be missed if the infant is not retested after early dismissal. In some states, other screening tests are performed in newborns to detect galactosemia (with an incidence of 1 in 50,000 births, this disorder involves a defect in the enzyme for converting glucose to galactose), hemoglobinopathies, and congenital adrenal hyperplasia.

Nearly 30,000 people in the United States have cystic fibrosis, a recessive disorder. It is carried by about 1 in 25 Caucasians in the United States, and these carriers often do not have a family history of cystic fibrosis. The clinical characteristics include pancreatic insufficiency (85% of patients), pulmonary disease characterized by recurrent infections and bronchiectasis, and failure to grow. In more than 60 percent of patients, the diagnosis is made during the first year of life. The gene associated with cystic fibrosis was identified in 1989 on chromosome 7, and encodes the protein cystic fibrosis transmembrane conductance regulator (CFTR), which is a chloride channel in cells. The failure of this channel to work properly causes excess chloride in sweat and changes in fluid balance, which in turn cause thickened mucus in the lungs. The most common defect in cystic fibrosis cells is the absence of phenylalanine in the protein. Testing is recommended for patients with a family history of cystic fibrosis and their partners. There are more than 150 mutations of the cystic fibrosis gene, and testing can detect 85 percent of the carriers.


Neural Tube Defects. Neural tube defects (NTDs) are the disorders most commonly screened for prenatally. The incidence of NTDs is between 1 in 1,000 and 2 in 1,000 births. A family history of NTDs and diabetes in the mother increases the risk significantly. If the mother's diet is supplemented with folic acid before conception, however, the incidence of NTDs decreases. These defects are associated with high mortality, high morbidity, and long-term developmental disability. They involve structural abnormalities of the spine, spinal cord, head, and brain.

In the United States, of every 1,000 pregnant females who are tested between 16 and 18 weeks' gestation, about 25 to 50 will have increased levels of maternal serum alpha-fetoprotein (msAFP) and 40 to 50 have low levels. The mothers with high levels of msAFP can undergo ultrasonography to assess gestational age, the presence of a multiple gestation, or significant abnormality. An alternative is to repeat the test within one to two weeks for mothers with abnormally high or low levels of the protein. If the repeat studies confirm the previous abnormal results, ultrasonography is then performed. After screening with ultrasonography, about 17 of the patients with increased levels of msAFP and 20 to 30 with low levels will have no findings that explain the abnormal values. Amniocentesis should be performed in these patients. Of the 17 patients with high levels, 1 or 2 will have a fetus with a significant NTD, whereas 1 in 65 of those with a low msAFP will have a fetus with a chromosome abnormality (1 in 90 chance of Down syndrome). For a pregnant female with an abnormally high msAFP level and a fetus with no NTD, the risk of stillbirth, low birth weight, neonatal death, and congenital anomalies is increased.

Other Disorders. The overall risk for recurrent cleft lip, with or without cleft palate, is 4 percent if a sibling or parent has the abnormality and 10 percent if it is present in two previous siblings. Lip pits or depressions on the lower lip of a newborn may be the manifestation of an autosomal dominant trait, and the recurrence rate for a sibling is 50 percent.

Generally, the incidence of multifactorial congenital disorders is less than 5 percent. The incidence of recurrence is 2 to 5 percent for cardiac anomalies, 1 to 2 percent for tracheoesophageal fistula, 1 to 2 percent for diaphragmatic hernia, 6 to 10 percent for hypospadias, and 4 to 8 percent for hip dislocation.


In North America, about 8 percent of pregnancies meet the criteria for performing amniocentesis or chorionic villous sampling. The following are basic points for prenatal testing:

  1. All patients have the right to receive information about the genetic risk associated with a pregnancy. This allows parents to make an informed choice about having a child with an abnormality.
  2. All patients have the right to refuse testing. What a patient decides to do about any given risk factor is entirely up to the patient. Genetic testing is voluntary except for what the state requires (e.g., neonatal screening for phenylketonuria, hypothyroidism, and other inborn errors of metabolism).
  3. Genetic screening is not expected to detect all genetic disorders in a given population.


Certain families have an increased risk for specific cancers. Many of these families have an identifiable gene associated with the disorder. Possession of the gene does not automatically mean that cancer will develop in the patient. The expression of most genes can be altered by environmental factors and by other genes. Consequently, a risk can be predicted only on the basis of the history of the gene being found in other families. If a family has a tendency for cancer, it is prudent to consult a geneticist (a list is available from the National Society of Genetic Counselors, 233 Canterbury Drive, Wallingford, PA 19080).

Breast Cancer Genes. BRCA1, a tumor-suppressor gene, accounts for 5 to 10 percent of all cases of breast cancer. It is autosomal dominant. A woman from a family prone to breast or ovarian cancer who carries certain mutations of BRCA1 has about an 80 percent chance that breast cancer will develop and a 40 to 60 percent chance of getting ovarian cancer. Members of a family with multiple cases of breast or ovarian cancer can be tested to determine whether they have a genetic alteration in BRCA1. If such an alteration is found, presymptomatic screening could be performed on other family members as part of a research protocol. Routine screening for mutations is not reasonable because nearly 100 different mutations of this gene have been identified, many of which are unique to specific families. Certain races, such as Ashkenazi Jews (European descent), have a high incidence of a site-specific mutation on BRCA1. Screening a specific population is not feasible because the patient may have other mutations in the gene, and even if a mutation were found, the implication of a mutated BRCA1 gene in a family not prone to cancer is not known.

A BRCA2 gene has been discovered and is thought to account for other genetically linked cases of breast cancer. This gene is associated with families with a history of cancer that have a high incidence of breast cancer among male family members. Patients with the genes need follow-up. The studies include breast self-examination monthly, breast examination by a physician semiannually, and mammography annually. Ovarian surveillance includes pelvic examination, ultrasonographic visualization of the ovaries, and measurement of the serum level of CA 125 for this cancer antigen. Prophylactic bilateral mastectomy and oophorectomy also can be considered as alternatives. One study revealed a 10 percent incidence of primary peritoneal cancers after prophylactic oophorectomy.

Colorectal Cancer. The two major forms of hereditary colon cancer are hereditary nonpolyposis colon cancer (HNPCC) and familial adenomatous polyposis (FAP). Four separate genes are associated with colon cancer. Management includes annual colonoscopy beginning at age twenty-five, or when the patient is ten years younger than the youngest relative discovered to have colon cancer. Flexible sigmoidoscopy is inadequate. Women should undergo transvaginal ultrasonography or endometrial biopsy annually. FAP, characterized by the appearance of hundreds of adenomas in the large bowel, accounts for 0.5 percent of colon cancers. Colon cancer develops in virtually 100 percent of patients with untreated FAP. Removal of the colon decreases the risk to 10 percent.


Sequencing of the human genome was completed in 2000. The completion of this task will speed the development of molecular genetic recognition and treatment. Readers can obtain useful information from the list of Internet sites included.

John W. Bachman

(see also: Environmental Determinants of Health; Genes; Genetic Disorders; Genetics and Health; Human Genome Project; Newborn Screening; Prenatal Care; Risk Assessment, Risk Management )


Centers for Disease Control and Prevention. Translating Advances in Human Genetics into Public Health Action: A Strategic Plan. Available at

Columbia-Presbyterian Medical Center. "Congenital Disorders. Screening for Neural Tube DefectsIncluding Folic Acid/Folate Prophylaxis." In Guide to Clinical Preventive Services, 2nd edition. Available at

Cystic Fibrosis Foundation. Facts about Cystic Fibrosis. Available at

Horowitz, M., ed. (2000). Basic Concepts in Medical Genetics: A Student's Survival Guide. New York: McGraw-Hill.

Human Genome Program of the U.S. Department of Energy. "Human Genome Project Information." Available at

National Down Syndrome Society. Education. Research. Advocacy: One Vision, One Voice. Available at

National Institutes of Health. "Office of Rare Diseases." Available at

National Library of Medicine and HRSA. Gene Tests. Available at

Nussbaum, R. L.; McInnes, R. R.; and Willard, H. F. Thompson and Thompson Genetics in Medicine, 6th edition. St. Louis, MO: W. B. Sanders.

Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The Genetics of Cancer. Available at

Turner's Syndrome Society of the United States. Available at

University of Kansas Medical Center. Genetics and Rare Conditions Site. Available at

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