Human Genetic Testing Applications

Diagnostic genetic testing is used to determine if your symptoms are being caused by a specific genetic condition. Genetic testing can also help rule out a genetic condition as the cause of symptoms. There are thousands of tests for diagnosing inherited genetic disorders. Many look at single genes such as those for cystic fibrosis, sickle cell disease, or specific forms of muscular dystrophy.

Many inherited disorders are identified indirectly by examining abnormalities in the genetic end products (proteins or metabolites) that are present in abnormal forms or quantities. Genes code for the production of thousands of proteins and, if there is a change in the code, changes can occur in the production of those proteins. So, rather than detecting the problem in the gene, some types of testing look for unusual findings related to the pertinent proteins. An example is hemophilia, a bleeding disorder. Screening may detect low levels of specific clotting factors (proteins that regulate blood clotting), which would suggest a bleeding disorder. This would be followed by testing for the genetic change that causes hemophilia when there is a desire to know the specific variant for testing of family members.

Some genetic tests are used to predict a disease that has not yet caused symptoms. These tests are most commonly used for individuals with a family history of genetic diseases that do not cause signs and symptoms until later in life, like Huntington disease and hereditary hemochromatosis.

Predictive genetic tests can also help assess the risk of developing a disease and allow individuals to take steps to prevent or minimize risks for the disease. For instance, women with a family history of breast or ovarian cancer may wish to be tested for BRCA1 and BRCA2 mutations, which are associated with an increased cancer risk.

Carrier testing is done to determine if someone carries a copy of a gene that could lead to a genetic disorder in their child if combined with a similar variant gene copy from their partner. Carrier testing may be offered when couples are planning a pregnancy or having their first visit for prenatal care. Carrier testing may also be done when an individual or a couple has a family history of an autosomal recessive disease.

A carrier with only one copy of an autosomal recessive variant usually will have no noticeable symptoms or only mild symptoms. But if their child inherits two copies, one from each parent, that child will have the disease. With each pregnancy, parents who carry a variant causing  the same autosomal recessive disease  have a one in four (25%) chance of having a child with that disease, and a 1 in 2 (50%) chance that their child will also carry the recessive gene copy but not have symptoms. There’s also a 1 in 4 chance (25%) that the child will not have the disease or be a carrier. Common carrier tests include those for Tay-Sachs disease, cystic fibrosis, and sickle-cell anemia.

Carrier testing may also be done to determine whether a woman carries a variant gene on one of her two X chromosomes that could lead to an X-linked recessive disorder in a child.

Prenatal genetic testing provides expecting parents information about a fetus’ potential genetic disorders. These tests most commonly look for aneuploidies, conditions in which there are extra or missing chromosomes.

Maternal blood tests to screen for chromosomal disorders are typically offered during the first and second trimesters. In addition to these conventional screenings, non-invasive cell-free fetal DNA screening may be offered. These tests look at the DNA released from the placenta that circulates in the woman’s blood stream. This non-invasive blood test can screen for Down syndrome, trisomy 13, trisomy 18, and disorders with sex chromosomes, starting at 10 weeks of pregnancy.

These tests are not diagnostic and should only serve as a starting point for further testing. If screening tests are positive, diagnostic tests may be done on the cells of the fetus or placenta. These are collected by amniocentesis or chorionic villus sampling. These tests do come with a small risk of pregnancy loss.

Every state requires newborn screening to test for treatable conditions that can cause serious developmental problems in infancy and childhood. These tests are done on a blood sample taken by pricking the child’s heel shortly after birth. While specific tests vary by state, newborn screening can include tests for congenital adrenal hyperplasia, a genetic disease that causes the hormone cortisol to be decreased in blood, phenylketonuria (PKU), an inherited autosomal recessive metabolic disorder, and hemoglobin disorders like sickle cell anemia. These tests look for chemicals that indicate genetic disorders, they do not test genes directly. When appropriate, abnormal blood screening tests in the newborn may be supplemented by genetic testing (as with PKU, for example).

Some of us respond differently than others to the same medications, or we may experience different side effects from the same drugs. The way we respond to medications can be due to the gene variations we have inherited. With respect to medications, our unique genetic make-up and our individual response may mean that a dose that is effective for one person may be less effective for another or that a dose that is safe for one person may be less safe for another person. Looking for genetic variations that may play a role in the over- or under-responsiveness to a therapeutic drug is called pharmacogenomics or pharmacogenetics.

Most pharmacogenomics tests currently look for variants in genes that code for drug-metabolizing enzymes. There are many enzymes in our bodies that metabolize or break down specific drugs, allowing them to be eliminated in urine or by other means. In some cases, decrease activity in an enzyme that metabolizes a medication may result in too much drug staying in the body. In other cases, individuals “hypermetabolize” drugs. This occurs when there is increased activity of an enzyme that breaks down the helpful drug too quickly, leading to a lack of response to the drug.

Some genetic changes are not inherited, but arise in an individual’s cells later in life and cannot be passed on to a person’s children. These are called somatic mutations and they underlie many forms of cancer. Somatic mutations can be caused by outside factors like sun damage, or smoking tobacco, but they often arise without a clear cause.

Genetic testing to identify somatic mutations can provide information on an individual’s prognosis and guide treatment. These tests are usually performed on a tumor sample, but may be performed on a blood sample (called a liquid biopsy).

Treatments that disrupt a specific step in cancer growth while causing minimal damage to normal cells are called targeted therapies; many of these therapies have companion diagnostic tests that demonstrate whether a tumor has the necessary mutation for the targeted therapy to be used. Cancers with certain somatic mutations may have a more predictable response to chemotherapy or targeted treatments than cancers without those mutations. Breast cancer, chronic myelogenous leukemia, lung cancer, and melanoma are a few examples of cancers that may be tested for specific mutations that predict a better response to targeted therapies.

Transplantation testing is used to tell whether an organ or tissue, such as a kidney, lung or bone marrow, is a match for the transplant between a donor and recipient. If it is not, a serious rejection reaction could occur between the transplant recipient and the donated organ or marrow.

Basic laboratory testing for tissue transplantation involves mixing the white blood cells (leukocytes) from the donor (or the donor tissue) and the recipient together and observing whether an immune response occurs. Although this technique is still commonly used, analysis of the DNA in both the donor and the recipient (tissue typing) is used to diminish the likelihood of rejection in the case of tissue transplantation.

A very specific set of genes is examined when DNA testing is used for tissue typing: a large set of genes called the “Major Histocompability Complex” or MHC on chromosome 6. These genes are highly variable between individuals and they code for the production of specific protein antigens located on the surface of many cells. It is these antigens that distinguish our own organs and tissues from those of another individual. These antigens have the ability to begin an immune system response that results in organ or tissue rejection if the tissue looks foreign.