Genetic Diseases - Genetic Testing

The most common form of genetic testing is screening of newborn infants for genetic abnormalities. In the United States, according to a 2003 report by the General Accounting Office (GAO), about four million newborns per year are screened by testing blood obtained from a prick of the newborn's heel within the first few days of life. Specific genetic disorders such as phenylketonuria (PKU) and other medical conditions that are not genetically linked, such as congenital hypothyroidism (underactive thyroid gland), can be found with heel-prick testing.

PKU is an inherited error of metabolism resulting from a deficiency of an enzyme called phenylalanine hydroxylase. The lack of this enzyme can produce mental retardation, organ damage, and postural problems. Children born with PKU must pay close attention to their diets so that they may lead healthy, normal lives.

Genetic screening is intended to identify disorders that require early detection and treatment to prevent serious illness or death. Each state determines which disorders to include in its screening program; the number chosen ranges from four to thirty-six, with eight or less being the most common. Table 6.1 shows the disorders most commonly included in screening programs and how many states require each. To help them decide, states generally consider criteria such as how often the disorder occurs in the population, whether an effective screening test exists, and whether the disorder is treatable. Table 6.2 shows the national incidence of, potential outcomes for, and treatment of each disease. States also may consider the cost of screening, which

TABLE 6.1
Disorders most commonly included in state newborn screening programs, 2002

Disorder	Number of states*
PKU	51
Congenital hypothyroidism	51
Galactosemia	50
Sickle cell diseases	44
Congenital adrenal hyperplasia	32
Biotinidase deficiency	24
Maple syrup urine disease	24
Homocystinuria	17
Note: This table does not include states that provide screening for the disorders to selected populations, as part of pilot programs, or by request.
*"States" refers to the 50 states and the District of Columbia.
SOURCE: "Table 1: Disorders Most Commonly Included in State Newborn Screening Programs, December 2002," in Newborn Screening: Characteristics of State Programs, U.S. General Accounting Office, Washington, DC, March 2003

TABLE 6.2
Information on disorders most commonly included in state newborn screening programs

Disorder	National incidence, 1990–99	Description	Potential outcomes	Treatment
Phenylketonuria	1 in 13,947	Deficiency of an enzyme needed to break down the amino acid phenylalanine	Mental retardation, seizures	Low-phenylalanine diet
Congenital hypothyroidism	1 in 3,044	Inability to produce adequate amount of thyroid hormone	Mental retardation, stunted growth	Thyroid hormone
Galactosemia	1 in 53,261	Deficiency of an enzyme needed to break down the milk sugar galactose	Brain damage, liver damage, cataracts, death	Galactose-free diet
Sickle cell diseases
Sicle cell anemia	1 in 3,721	Inherited blood disorder causing hemoglobin abnormalities	Organ damage, delayed growth, stroke	Penicillin, vaccinations
Hemoglobin sickle C disease	1 in 7,386
Congenital adrenal hyperplasia	1 in 18,987	Deficiency of an adrenal enzyme needed to produce cortisol and aldosterone	Death due to salt loss, reproductive and growth difficulties	Hormone replacement and salt replacement
Biotinidase deficiency	1 in 61,319	Deficiency of the enzyme biotinidase, needed to recycle the vitamin biotin	Mental retardation, developmental delay, seizures, hearing loss	Biotin supplements
Maple syrup urine disease	1 in 230,028	Deficiency of the enzyme needed to metabolize leucine, isoleucine, and valine	Mental retardation, seizures, coma, death	Dietary management and supplements
Homocystinuria	1 in 343,650	Deficiency of the enzyme needed to metabolize the amino acid homocysteine	Mental retardation, eye problems, skeletal abnormalities, stroke	Dietary management and vitamin supplements
SOURCE: "Appendix III: Information on Disorders Most Commonly Included in State Newborn Screening Programs," in Newborn Screening: Characteristics of State Programs, U.S. General Accounting Office, Washington, DC, March 2003

may include costs associated with doing more tests, acquiring and implementing new technology, and following up on abnormal test results. According to a GAO report on state newborn screening measures, more than $120 million total was spent on newborn screening in state fiscal year 2001.

There are thousands of genetic diseases, such as sickle cell anemia, CF, and Tay-Sachs disease (TSD), that may be passed from one generation to the next. Genetic testing to determine whether an individual has a gene that if passed onto offspring may produce disease is called carrier identification.

Prenatal genetic testing enables physicians to diagnose diseases in the fetus. Using samples of genetic material obtained from amniocentesis or chorionic villus sampling, physicians can detect disease in an unborn child. Down syndrome is the genetic disease most often identified prenatally.

Genetic testing also can be performed postnatally (after birth) to determine which children and adults are at increased risk of developing specific diseases. Scientists can perform predictive genetic testing to identify which individuals are at risk for CF, TSD, Huntington's disease, amyotrophic lateral sclerosis (ALS; a degenerative neurologic condition commonly known as Lou Gehrig's disease), and several types of cancers (including some cases of breast, colon, and ovarian cancer).

More than 1,000 genetic tests are currently available, but public health professionals do not consider it practical to screen for conditions that are very rare, those that have only minor health consequences, or those for which there is still no effective treatment. Table 6.3 lists selected diseases for which gene tests are currently available.

A positive test result (the presence of a defective or altered gene) from predictive genetic testing does not guarantee that the individual will develop the disease; it simply identifies the individual as genetically susceptible and at increased risk for developing the disease. For example, a woman who tests positive for the BRCA1 gene has about an 80 percent chance of developing breast cancer before age sixty-five. It is also important to note that like other types of diagnostic medical testing, genetic tests are not 100 percent predictive—the results rely on the quality of laboratory procedures and accuracy of interpretations. Further, because tests vary in their sensitivity and specificity, there is always the possibility of false-positive and false-negative test results.

Researchers hope that positive test results will encourage people at higher-than-average risk of developing a disease to be especially vigilant about disease prevention and screening to detect the disease early, when it can be treated most successfully.

TABLE 6.3
Selected diseases for which gene tests are available

Alpha-1-antitrypsin deficiency (AAT; emphysema and liver disease)

Amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease; progressive motor function loss leading to paralysis and death)

Alzheimer's disease (APOE; late-onset variety of senile dementia)

Ataxia telangiectasia (AT; progressive brain disorder resulting in loss of muscle control and cancers)

Gaucher disease (GD; enlarged liver and spleen, bone degeneration)

Inherited breast and ovarian cancer (BRCA 1 and 2; early-onset tumors of breasts and ovaries)

Hereditary nonpolyposis colon cancer (CA; early-onset tumors of colon and sometimes other organs)

Charcot-Marie-Tooth (CMT; loss of feeling in ends of limbs)

Congenital adrenal hyperplasia (CAH; hormone deficiency; ambiguous genitalia and male pseudohermaphroditism)

Cystic fibrosis (CF; disease of lung and pancreas resulting in thick mucous accumulations and chronic infections)

Duchenne muscular dystrophy/Becker muscular dystrophy (DMD; severe to mild muscle wasting, deterioration, weakness)

Dystonia (DYT; muscle rigidity, repetitive twisting movements)

Fanconi anemia, group C (FA; anemia, leukemia, skeletal deformities)

Factor V-Leiden (FVL; blood-clotting disorder)

Fragile X syndrome (FRAX; leading cause of inherited mental retardation)

Hemophilia A and B (HEMA and HEMB; bleeding disorders)

Hereditary hemochromatosis (HFE; excess iron storage disorder)

Huntington's disease (HD; usually midlife onset; progressive, lethal, degenerative neurological disease)

Myotonic dystrophy (MD; progressive muscle weakness; most common form of adult muscular dystrophy)

Neurofibromatosis type 1 (NF1; multiple benign nervous system tumors that can be disfiguring; cancers)

Phenylketonuria (PKU; progressive mental retardation due to missing enzyme; correctable by diet)

Adult polycystic kidney disease (APKD; kidney failure and liver disease)

Prader Willi/Angelman syndromes (PW/A; decreased motor skills, cognitive impairment, early death)

Sickle cell disease (SS; blood cell disorder; chronic pain and infections)

Spinocerebellar ataxia, type 1 (SCA1; involuntary muscle movements, reflex disorders, explosive speech)

Spinal muscular atrophy (SMA; severe, usually lethal progressive muscle-wasting disorder in children)

Thalassemias (THAL; anemias—reduced red blood cell levels)

Tay-Sachs disease (TS; fatal neurological disease of early childhood; seizures, paralysis)

SOURCE: "Some Currently Available DNA-Based Gene Tests," in Human Genome Project Information, U.S. Department of Energy Office of Science, Office of Biological and Environmental Research, Human Genome Program, Washington, DC, December 2003 [Online] http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetest.shtml [accessed June 25, 2004]

Ethical Considerations

As scientists learn more about the genes responsible for a variety of illnesses, they can design tests to predict whether an individual is at risk of developing the disease. The ethical issues involved in genetic testing have turned out to be far more complicated than originally anticipated.

Initially, physicians believed that a test to determine in advance who would develop or escape a disease would be welcomed by at-risk families. They would be able to plan more realistically about having children, choosing jobs, obtaining insurance, and living their lives. Nevertheless, many people with family histories of a genetic disease have decided that not knowing is better than anticipating a grim future and an agonizing, slow death. They prefer to live with the hope that they will not develop the disease rather than the certain knowledge that they will.

There are also concerns about privacy and the confidentiality of medical records and the results of genetic testing. Some people are reluctant to be tested because they fear they may lose their health, life, and disability insurance, or even their jobs, if they are found to be at risk for a disease. Genetic tests are sometimes costly, and some insurers agree to reimburse for testing only if they are informed of the results. Insurance companies believe they cannot risk selling policies to people they know will become disabled or die prematurely.

The discovery of genetic links and the development of tests to predict the likelihood or certainty of developing a disease raise ethical questions for people who carry a defective gene. Should women who are carriers of Huntington's disease or CF have children? Should a fetus with the defective gene be carried to term or aborted? One health insurance company agreed to pay for prenatal CF testing for a mother who already had one affected child, but the company insisted if the baby was affected, the mother would have to terminate the pregnancy or it would not cover the child's future medical bills.