Genetic testing

SIGNIFICANCE: Genetic testing comprises any procedure used to detect the presence of a genetic disorder or a defective gene in a fetus, newborn, or adult. The results of genetic tests can be useful in family planning, treatment decisions, and medical research. Genetic testing has significant implications with respect to reproductive choices, privacy, insurance coverage, and employment.

Prenatal Diagnosis

Prenatal diagnosis is the testing of a developing fetus in the womb, or uterus, for the presence of a genetic disorder. Potential limitations on prenatal diagnosis depend on the country and its policies. In the United States, prenatal diagnosis is typically limited to high-risk individuals and is usually recommended only if an individual is thirty-five years of age or older, if they have had two or more spontaneous abortions, or if they or their partner has a family history of a genetic disorder; the American College of Obstetricians and Gynecologists (ACOG) has recommended for many years that prenatal diagnosis be offered to all pregnant people regardless of age. Hundreds of genetic disorders can be tested in a fetus. One of the most common genetic disorders screened for is Down syndrome, or 21, which is caused by having an extra copy of chromosome 21. The incidence of Down syndrome increases sharply in children born to individuals over the age of forty.

One technique used for prenatal diagnosis is amniocentesis. In most countries, it is typically performed between the fifteenth and twentieth weeks of pregnancy. Amniocentesis involves the insertion of a hypodermic needle through the abdomen into the uterus of a pregnant person. The insertion of the needle is guided by ultrasound, a machine that uses high-frequency sound waves to locate a developing fetus or internal organs and presents a visual image on a video monitor. A small amount of amniotic fluid, which surrounds and protects the fetus, is withdrawn. The amniotic fluid contains fetal secretions and cells sloughed off the fetus that are analyzed for genetic abnormalities.

Chromosomal disorders such as Down syndrome, Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13) can be detected by examining the chromosome number of the fetal cells. Certain biochemical disorders such as Tay-Sachs disease, a progressive disorder characterized by a startle response to sound, blindness, paralysis, and death in infancy, can be determined by testing for the presence or absence of a specific enzyme activity in the amniotic fluid. Amniocentesis can also determine the sex of a fetus and detect common birth defects such as spina bifida (an open or exposed spinal cord) and anencephaly (partial or complete absence of the brain) by measuring levels of alpha fetoprotein in the amniotic fluid. The limitations of amniocentesis include inability to detect most genetic disorders, possible fetal injury or miscarriage, infection, and bleeding.

Chorionic villus sampling (CVS) is another technique used for prenatal diagnosis. It is performed earlier than amniocentesis (while in some countries such as the United States it is performed between the tenth and thirteenth weeks of pregnancy, in others it is not performed before the eleventh week). Under the guidance of ultrasound, a catheter is inserted into the uterus via the cervix to obtain a sample of the chorionic villi. The chorionic villi are part of the fetal portion of the placenta, the organ that nourishes the fetus. The chorionic villi can be analyzed for chromosomal and biochemical disorders but not for congenital birth defects such as spina bifida and anencephaly. The limitations of this technique are inaccurate diagnosis and a slightly higher chance of fetal loss than in amniocentesis.

Beginning in 2011, cell-free fetal DNA testing became available as a type of noninvasive prenatal genetic screening in the United States, and many other countries began to offer this type of testing over subsequent years. Cell-free fetal DNA testing involves a simple blood draw from a pregnant woman; the blood is then analyzed for pieces of fetal DNA that have passed into the expectant mother's bloodstream. Cell-free fetal DNA testing carries fewer risks than amniocentesis or CVS but does not offer a complete diagnosis. A growing number of pregnant people are opting for cell-free fetal DNA testing first and then undergoing amniocentesis if the results of the cell-free test indicate there is a risk for a genetic disorder to get an accurate diagnosis; however, some health experts have recommended that women at higher risk of having a baby with a chromosomal disorder or who are expecting more than one baby use an alternate method of screening. By the 2020s, some teams of researchers were attempting to develop a more extensive form of cell-free fetal DNA testing that would further reduce the need for amniocentesis or other invasive procedures.

Neonatal Testing

The most widespread genetic testing is the mandatory testing of every newborn infant for the inborn error of metabolism (a biochemical disorder caused by mutations in the genes that code for the synthesis of enzymes) phenylketonuria (PKU), a disorder in which the enzyme for converting phenylalanine to tyrosine is nonfunctional. The purpose of this type of testing is to initiate early treatment of infants to prevent brain damage and permanent intellectual disabilities. A blood sample is taken by heel prick from a newborn in the hospital nursery, placed on filter papers as dried spots, and subsequently tested, using the Guthrie test, for abnormally high levels of phenylalanine. In infants who test positive for PKU, a diet low in phenylalanine is initiated within the first two months of life. Newborns can be tested for many other disorders, such as sickle-cell disease and galactosemia (accumulation of galactose in the blood).

Carrier Testing

A healthy couple contemplating having children can be tested voluntarily to determine if they carry a gene for a disorder that runs in the family. This type of screening test is known as carrier testing because it is designed for carriers (individuals who have a normal gene paired with a defective allele of the same gene but have no symptoms of a genetic disorder). Carriers of the genes responsible for Tay-Sachs disease, cystic fibrosis (accumulation of mucus in the lungs and pancreas), Duchenne muscular dystrophy (wasting away of muscles), and hemophilia (uncontrolled bleeding caused by lack of blood clotting factor) can be detected by DNA analysis.

When the gene responsible for a specific genetic disorder is unknown, the location of the gene on a chromosome can be detected indirectly by linkage analysis. Linkage analysis is a technique in which geneticists look for consistent patterns in large families where the mutated gene and a genetic marker always appear together in affected individuals and those known to be carriers. If a genetic marker lies close to the defective gene, it is possible to locate the defective gene by looking for the genetic marker. The genetic markers used commonly for linkage analysis are restriction fragment length polymorphisms (RFLPs). When human DNA is isolated from a blood sample and digested at specific sites with special enzymes called restriction endonucleases, RFLPs are produced. RFLPs are found scattered randomly in human DNA and are of different lengths in different people, except in identical twins. They are caused by mutations or the presence of varying numbers of repeated copies of a DNA sequence and are inherited. RFLPs are separated by gel electrophoresis, a technique in which DNA fragments of varying lengths are separated in an electric field according to their sizes. The separated DNA fragments are blotted onto a nylon membrane, a process known as Southern blotting. The membrane is probed and then visualized on X-ray film. The characteristic pattern of DNA bands visible on the film is similar in appearance to the bar codes on grocery items.

An early successful example of linkage analysis involved the search for the gene that causes Huntington’s disease, an always fatal neurological disease that typically shows onset after thirty-five or forty years of age. In 1983, James Gusella, Nancy Wexler, and Michael Conneally reported a correlation between one specific RFLP they named G8 and Huntington’s disease (Huntington’s chorea). After studying numerous RFLPs of generations of an extended Venezuelan family with a history of Huntington’s disease, they discovered that G8 was present in members afflicted with the genetic disorder and was absent in unaffected members.

High-risk individuals or families can be tested voluntarily for the presence of a mutated gene that may indicate a predisposition to a late-onset genetic disorder such as Alzheimer’s disease or to other conditions such as hereditary breast, ovarian, and colon cancers. This type of testing is called predictive testing. Unlike tests for many of the inborn errors of metabolism, predictive testing can give only a rough idea of how likely an individual may be to develop a particular disease. It is not always clear how such information should be used, but at least in some cases, lifestyle or therapeutic changes can be instituted to lessen the likelihood of developing the disease.

Impact and Applications

Genetic testing has had a significant impact on families and society at large. It provides objective information to families about genetic disorders or birth defects and provides an analysis of the risks for genetic disorders through genetic counseling. Consequently, many prospective parents are able to make informed and responsible decisions about conception and birth. Some choose not to bear children, some terminate pregnancy after prenatal diagnosis, and some may opt to use in vitro fertilization in conjunction with preimplantation genetic screening. Genetic testing can have a profound psychological impact on an individual or family. A positive genetic test could cause a person to experience depression, while a negative test result may eliminate anxiety and distress. Questions have been raised in the scientific and medical community about the reliability and high costs of tests. There is concern about whether genetic tests are stringent enough to ensure that errors are not made. DNA-based diagnosis can lead to errors if DNA samples are contaminated. Such errors can be devastating to families. People at risk for late-onset disorders such as Huntington’s disease can be tested to determine if they are predisposed to developing the disease. There is, however, controversy over whether it is ethical to test for diseases for which there are no known cures or preventive therapies. The question of testing also creates a dilemma in many families. Unlike other medical tests, predictive testing involves the participation of many members of a family. Some members of a family may wish to know their genetic status, while others may not.

While there has been great enthusiasm over genetic testing, there are also social, legal, and ethical issues such as discrimination, confidentiality, reproductive choice, and abuse of genetic information. Insurance companies and employers may require prospective customers and employees to submit to genetic testing or may inquire about a person’s genetic status. Individuals may be denied life insurance coverage because of their genetic status, or a prospective customer may be forced to pay exorbitant insurance premiums. The potential for discrimination with respect to employment and promotions also exists.

As genetic testing has become more standard practice, the potential for misuse of genetic tests and genetic information has become greater. Prospective parents may potentially use prenatal diagnosis as a means to ensure the birth of a “perfect” child. Restriction fragment length polymorphism analysis, used in genetic testing, has applications in DNA fingerprinting or DNA typing. DNA fingerprinting is a powerful tool for identification of individuals used to generate patterns of DNA fragments unique to each individual based on differences in the sizes of repeated DNA regions in humans. It is used to establish identity or nonidentity in immigration cases and paternity and maternity disputes; it is also used to exonerate the innocent accused of violent crimes and to link a suspect’s DNA to body fluids or hair left at a crime scene. Several states in the United States have been collecting blood samples from a variety of sources, including newborn infants during neonatal testing and individuals convicted of violent crimes, and have been storing genetic information derived from them in DNA databases for future reference. Such information could be misused by unauthorized people.

Key terms

• genetic disordera disorder caused by a mutation in a gene or chromosome
• genetic markera distinctive DNA sequence that shows variation in the population and can therefore potentially be used for identification of individuals and for discovery of disease genes

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