What is genetic testing?

Genetic testing is a type of medical test that looks for changes in your DNA. DNA is short for deoxyribonucleic acid. It contains the genetic instructions in all living things. Genetic tests analyze your cells or tissue to look for any changes in

• Genes, which are parts of DNA that carry the information needed to make a protein
• Chromosomes, which are thread-like structures in your cells. They contain DNA and proteins.
• Proteins, which do most of the work in your cells. Testing can look for changes in the amount and activity level of proteins. If it finds changes, it might be due to changes in your DNA.

Why is genetic testing done?

Genetic testing may be done for many different reasons, including to

• Find genetic diseases in unborn babies. This is one type of prenatal testing.
• Screen newborn babies for certain treatable conditions
• Lower the risk of genetic diseases in embryos that were created using assisted reproductive technology
• Find out if you carry a gene for a certain disease that could be passed on to your children. This is called carrier testing.
• See whether you are at increased risk of developing a specific disease. This may be done for a disease that runs in your family.
• Diagnose certain diseases
• Identify genetic changes that may be causing or contributing to a disease that you were already diagnosed with
• Figure out how severe a disease is
• Help guide your doctor in deciding the best medicine and dosage for you. This is called pharmacogenomic testing.

How is genetic testing done?

Genetic tests are often done on a blood or cheek swab sample. But they may also be done on samples of hair, saliva, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. The sample is sent to a laboratory. There, a lab technician will use one of several different techniques to look for genetic changes.

What are the benefits of genetic testing?

The benefits of genetic testing include

• Helping doctors make recommendations for treatment or monitoring
• Giving you more information for making decisions about your health and your family's health:
  • If you find out that you are at risk for a certain disease, you might take steps to lower that risk. For example, you may find out that you should be screened for a disease earlier and more often. Or you might decide to make healthy lifestyle changes.
  • If you find out that you are not at risk for a certain disease, then you can skip unnecessary checkups or screenings
  • A test could give you information that helps you make decisions about having children
• Identifying genetic disorders early in life so treatment can be started as soon as possible

What are the drawbacks of genetic testing?

The physical risks of the different types of genetic testing are small. But there can be emotional, social, or financial drawbacks:

• Depending on the results, you may feel angry, depressed, anxious, or guilty. This can be especially true if you are diagnosed with a disease that does not have effective treatments.
• You may be worried about genetic discrimination in employment or insurance
• Genetic testing may give you limited information about a genetic disease. For example, it cannot tell you whether you will have symptoms, how severe a disease might be, or whether a disease will get worse over time.
• Some genetic tests are expensive, and health insurance might only cover part of the cost. Or they may not cover it at all.

How do I decide whether to be tested?

The decision about whether to have genetic testing is complex. In addition to discussing the test with your health care provider, you can meet with a genetic counselor. Genetic counselors have specialized degrees and experience in genetics and counseling. They can help you understand the tests and weigh the risks and benefits. If you do get a test, they can explain the results and make sure that you have the support that you need.

Genetic testing is a type of medical test that identifies changes in genes, chromosomes, or proteins. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. More than 77,000 genetic tests are currently in use, and others are being developed.

Genetic testing involves looking for changes in:

• Genes: Gene tests study DNA sequences to identify variations (mutations) in genes that can cause or increase the risk of a genetic disorder. Gene tests can be narrow or large in scope, analyzing an individual DNA building block (nucleotide), one or more genes, or all of a person’s DNA (which is known as their genome).
• Chromosomes: Chromosomal genetic tests analyze whole chromosomes or long lengths of DNA to see if there are large genetic changes, such as an extra copy of a chromosome, that cause a genetic condition.
• Proteins: Biochemical genetic tests study the amount or activity level of proteins or enzymes; abnormalities in either can indicate changes to the DNA that result in a genetic disorder.

Genetic testing is voluntary. Because testing has benefitsas well as limitations and risks, the decision about whether to be tested is a personal and complex one. A geneticist or genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing.

Genetic testing uses laboratory methods to look at your genes, which are the DNA instructions you inherit from your mother and your father.

How are genetic tests used?

Genetic tests may be used to identify increased risks of health problems, to choose treatments, or to assess responses to treatments.

What can I learn?

There are many different types of genetic tests. Genetic tests can help to:

• Diagnose disease

• Identify gene changes that are responsible for an already diagnosed disease

• Determine the severity of a disease

• Guide doctors in deciding on the best medicine or treatment to use for certain individuals

• Identify gene changes that may increase the risk to develop a disease

• Identify gene changes that could be passed on to children

• Screen newborn babies for certain treatable conditions

Genetic test results can be hard to understand, however specialists like geneticists and genetic counselors can help explain what results might mean to you and your family. Because genetic testing tells you information about your DNA, which is shared with other family members, sometimes a genetic test result may have implications for blood relatives of the person who had testing.

What are the different types tests?

Diagnostic testing is used to precisely identify the disease that is making a person ill. The results of a diagnostic test may help you make choices about how to treat or manage your health.

Predictive and pre-symptomatic genetic tests are used to find gene changes that increase a person's likelihood of developing diseases. The results of these tests provide you with information about your risk of developing a specific disease. Such information may be useful in decisions about your lifestyle and healthcare.

Carrier testing is used to find people who "carry" a change in a gene that is linked to disease. Carriers may show no signs of the disease; however, they have the ability to pass on the gene change to their children, who may develop the disease or become carriers themselves. Some diseases require a gene change to be inherited from both parents for the disease to occur. This type of testing usually is offered to people who have a family history of a specific inherited disease or who belong to certain ethnic groups that have a higher risk of specific inherited diseases.

Prenatal testing is offered during pregnancy to help identify fetuses that have certain diseases.

Newborn screening is used to test babies one or two days after birth to find out if they have certain diseases known to cause problems with health and development.

Pharmacogenomic testing gives information about how certain medicines are processed by an individual's body. This type of testing can help your healthcare provider choose the medicines that work best with your genetic makeup.

Research genetic testing is used to learn more about the contributions of genes to health and to disease. Sometimes the results may not be directly helpful to participants, but they may benefit others by helping researchers expand their understanding of the human body, health, and disease.

What are the benefits and drawbacks?

Benefits: Genetic testing may be beneficial whether the test identifies a mutation or not. For some people, test results serve as a relief, eliminating some of the uncertainty surrounding their health. These results may also help doctors make recommendations for treatment or monitoring, and give people more information for making decisions about their and their family's health, allowing them to take steps to lower his/her chance of developing a disease. For example, as the result of such a finding, someone could be screened earlier and more frequently for the disease and/or could make changes to health habits like diet and exercise. Such a genetic test result can lower a person's feelings of uncertainty, and this information can also help people to make informed choices about their future, such as whether to have a baby.

Drawbacks: Genetic testing has a generally low risk of negatively impacting your physical health. However, it can be difficult financially or emotionally to find out your results.

Emotional: Learning that you or someone in your family has or is at risk for a disease can be scary. Some people can also feel guilty, angry, anxious, or depressed when they find out their results.

Financial: Genetic testing can cost anywhere from less than $100 to more than $2,000. Health insurance companies may cover part or all of the cost of testing.

Many people are worried about discrimination based on their genetic test results. In 2008, Congress enacted the Genetic Information Nondiscrimination Act (GINA) to protect people from discrimination by their health insurance provider or employer. GINA does not apply to long-term care, disability, or life insurance providers.

Limitations of testing: Genetic testing cannot tell you everything about inherited diseases. For example, a positive result does not always mean you will develop a disease, and it is hard to predict how severe symptoms may be. Geneticists and genetic counselors can talk more specifically about what a particular test will or will not tell you, and can help you decide whether to undergo testing.

How do I decide whether to be tested?

There are many reasons that people might get genetic testing. Doctors might suggest a genetic test if patients or their families have certain patterns of disease. Genetic testing is voluntary and the decision about whether to have genetic testing is complex.

A geneticist or genetic counselor can help families think about the benefits and limitations of a particular genetic test. Genetic counselors help individuals and families understand the scientific, emotional, and ethical factors surrounding the decision to have genetic testing and how to deal with the results of those tests.

Your doctor may suggest a genetic test to detect your risk of certain health problems, such as cancer. If you have symptoms of a disease, a genetic test may help with diagnosis.

Genetic testing looks for changes in genes. It’s usually done in a lab using a blood sample. Thousands of genetic tests are currently available.

Deciding whether to get a genetic test isn’t easy. It’s important to consider what you may learn. Test results can be a relief. They may give you peace of mind to know that you don’t carry a genetic change linked to a certain disease.

But test results can be alarming, too. Learning that you’re at risk of developing a certain disease may make the future seem uncertain. Keep in mind that such results may not mean that you’ll get that disease.

Genetic counselors are one type of health professional who can help you understand the risks and benefits of genetic testing. Your doctor may refer you to one. They can help you decide whether to undergo testing. And they can help explain what test results mean.

Many types of genetic tests are available to analyze changes in genes, chromosomes, or proteins. A health care provider will consider several factors when selecting the appropriate test, including what condition or conditions are suspected and the genetic variations typically associated with those conditions. If a diagnosis is unclear, a test that looks at many genes or chromosomes may be used. However, if a specific condition is suspected, a more focused test may be done.

There are several types of genetic tests:

Molecular tests look for changes in one or more genes. These types of tests determine the order of DNA building blocks (nucleotides) in an individual's genetic code, a process called DNA sequencing. These tests can vary in scope:

• Targeted single variant: Single variant tests look for a specific variant in one gene. The selected variant is known to cause a disorder (for example, the specific variant in the HBB gene that causes sickle cell disease). This type of test is often used to test family members of someone who is known to have a particular variant, to determine whether they have a familial condition. Also, direct-to-consumer genetic testing companies typically analyze a number of specific variants in particular genes (rather than finding all the variants in those genes) when providing health or disease risk information.
• Single gene: Single gene tests look for any genetic changes in one gene. These tests are typically used to confirm (or rule out) a specific diagnosis, particularly when there are many variants in the gene that can cause the suspected condition.
• Gene panel: Panel tests look for variants in more than one gene. This type of test is often used to pinpoint a diagnosis when a person has symptoms that may fit a wide array of conditions, or when the suspected condition can be caused by variants in many genes. (For example, there are hundreds of genetic causes of epilepsy.)
• Whole exome sequencing/whole genome sequencing: These tests analyze the bulk of an individual’s DNA to find genetic variations. Whole exome or whole genome sequencing is typically used when single gene or panel testing has not provided a diagnosis, or when the suspected condition or genetic cause is unclear. Whole exome or whole genome sequencing is often more cost- and time-effective than performing multiple single gene or panel tests.

Chromosomal tests analyze whole chromosomes or long lengths of DNA to identify large-scale changes. Changes that can be found include an extra or missing copy of a chromosome (trisomy or monosomy, respectively), a large piece of a chromosome that is added (duplicated) or missing (deleted), or rearrangements (translocations) of segments of chromosomes. Certain genetic conditions are associated with specific chromosomal changes, and a chromosomal test can be used when one of these conditions is suspected. (For example, Williams syndrome is caused by a deletion of a section of chromosome 7.)

Gene expression tests look at which genes are turned on or off (expressed) in different types of cells. When a gene is turned on (active), the cell produces a molecule called mRNA from the instructions in the genes, and the mRNA molecule is used as a blueprint to make proteins. Gene expression tests study the mRNA in cells to determine which genes are active. Too much activity (overexpression) or too little activity (underexpression) of certain genes can be suggestive of particular genetic disorders, such as many types of cancer.

Biochemical tests do not directly analyze DNA, but they study the amount or activity level of proteins or enzymes that are produced from genes. Abnormalities in these substances can indicate that there are changes in the DNA that underlie a genetic disorder. (For example, low levels of biotinidase enzyme activity is suggestive of biotinidase deficiency, which is caused by BTD gene variants.)

Genetic testing can provide information about a person's genetic background. The uses of genetic testing include:

Newborn screening

Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. Millions of babies are tested each year in the United States. The U.S. Health Services and Resource Administration recommends that states screen for a set of 35 conditions, which many states exceed.

Diagnostic testing

Diagnostic testing is used to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed before birth or at any time during a person's life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person's choices about health care and the management of the disorder.

Carrier testing

Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple's risk of having a child with a genetic condition.

Prenatal testing

Prenatal testing is used to detect changes in a fetus's genes or chromosomes before birth. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple's uncertainty or help them make decisions about a pregnancy. It cannot identify all possible inherited disorders and birth defects, however.

Preimplantation testing

Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a specialized technique that can reduce the risk of having a child with a particular genetic or chromosomal disorder. It is used to detect genetic changes in embryos that were created using assisted reproductive techniques (ART) such as in-vitro fertilization (IVF). In-vitro fertilization involves removing egg cells from a woman’s ovaries and fertilizing them with sperm cells outside the body. To perform preimplantation testing, a small number of cells are taken from these embryos and tested for certain genetic changes. Only embryos without these changes are implanted in the uterus to initiate a pregnancy.

Predictive and presymptomatic testing

Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person's risk of developing disorders with a genetic basis, such as certain types of cancer. Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hereditary hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder and help with making decisions about medical care.

Forensic testing

Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).

Genetic testing is available for hereditary breast and ovarian cancer. Most breast and ovarian cancer is not caused by inherited mutations, so genetic testing will not help most women with a family health history of breast and ovarian cancer. Genetic testing will not identify the cause for some hereditary breast and ovarian cancers, because the genes affected in these cancers are not yet known.

Genetic counseling before genetic testing for hereditary breast and ovarian cancer is important to determine whether you and your family are likely enough to have a mutation that it is worth getting tested. Usually, genetic testing is recommended if you have:

• A strong family health history of breast and ovarian cancer
• A moderate family health history of breast and ovarian cancer and are of Ashkenazi Jewish or Eastern European ancestry
• A personal history of breast cancer and meet certain criteria (related to age of diagnosis, type of cancer, presence of certain other cancers or cancer in both breasts, ancestry, and family health history)
• A personal history of ovarian, fallopian tube, or primary peritoneal cancer
• A known BRCA1, BRCA2, or other inherited mutation in your family

Genetic testing for hereditary breast and ovarian cancer looks for mutations in the BRCA1 and BRCA2 genes. Your doctor might suggest testing using a multigene panel, which looks for mutations in several genes at the same time, including BRCA1 and BRCA2. If you are of Ashkenazi Jewish or Eastern European ancestry, your doctor might suggest testing for three specific BRCA1 and BRCA2 mutations, called founder mutations. These are the most common mutations in people of Ashkenazi Jewish or Eastern European ancestry.

The BRCA1 and BRCA2 genes

The breast cancer 1(BRCA1) and breast cancer 2(BRCA2) genes are the genes most commonly affected in hereditary breast and ovarian cancer. Normally, the BRCA1 and BRCA2 genes protect you from getting certain cancers. But certain mutations in the BRCA1 and BRCA2 genes prevent them from working properly, so that if you inherit one of these mutations, you are more likely to get breast, ovarian, and other cancers. You and your family members are more likely to have a BRCA1 or BRCA2 mutation if your family has a strong history of breast or ovarian cancer. Because BRCA1 and BRCA2 mutations are inherited, family members with BRCA1 or BRCA2 mutations usually share the same mutation.

The genetic counselor can help you determine the best testing strategy for you and your family. Whenever possible, the first person tested in your family should be someone who has had breast, ovarian, or another BRCA-related cancer. If none of your family members who have had one of these cancers are available for genetic testing, then genetic testing can start with an unaffected person. However, the test results might not be as helpful.

Genetic counseling after genetic testing is important to help you understand your test results and decide the next steps for you and your family:

• If you have a positive test result, the test showed that you have a mutation known to cause hereditary breast and ovarian cancer.
  • What it means for you:
    • You can take steps to make it less likely that you will get cancer or to find cancer early if you do get it.
    • If you have already had breast or ovarian cancer, a positive test result can help guide your treatment decisions.
  • What it means for your family:
    • If other family members decide to get genetic testing, their test should check for the same mutation you have.
    • Your parents, children, sisters, and brothers each have a 1 in 2 (50%) chance of having the same mutation.
• If you have a negative test result, the test didn’t find a mutation. However, what this means for you depends on whether you have already had breast or ovarian cancer and whether another relative is known to have a mutation.
  • If you have already had breast or ovarian cancer:
    • What it means for you:
      • A negative result means that the test did not find a mutation that caused your cancer.
      • Further testing might be available.
    • What it means for your family:
      • The breast and ovarian cancer in your family is less likely to be due to an inherited mutation, unless another relative is known to have a mutation.
      • Genetic testing in your family members who have not had breast or ovarian cancer is unlikely to be helpful, unless another relative is known to have a mutation.
      • In some cases testing might still be helpful for another family member who has had breast or ovarian cancer. This is because it is still possible that there is an inherited mutation in your family, but you did not inherit it.
  • If you have not had breast or ovarian cancer:
    • What it means for you:
      • If a mutation has not already been found in another family member:
        • A negative test result is considered uninformative because the result could mean that:
          • • The breast and ovarian cancers in your family are caused by one of the mutations included in the genetic test but you did not inherit the mutation.
              OR
            • The breast and ovarian cancers in your family were not caused by a mutation that was included in the genetic test.
      • • You are still considered at increased risk for the cancers that run in your family. The level of risk, appropriate screening and prevention options, and need for additional genetic testing will vary for each person and each family.
    • • If a mutation has already been found in another family member and the test showed you do not have the mutation:
        • You are not at higher risk than the average person for breast or ovarian cancer. You also cannot pass the mutation on to your children.
• If you have a variant of uncertain significance (VUS) result, the test found a mutation in one of the genes associated with hereditary breast and ovarian cancer, but whether that specific mutation causes cancer is unknown. Some mutations prevent genes from working properly, while others have no effect. It is not always easy to tell whether or not a mutation in a gene has a harmful effect.
  • What it means for you:
    • If you have already had breast or ovarian cancer, it is unclear whether the mutation found in the test caused your cancer. Further testing might be available.
    • Whether or not you have already had breast or ovarian cancer, you are still considered at increased risk for the cancers that run in your family. The level of risk, appropriate screening and prevention options, and need for additional genetic testing will vary for each person and each family.

Having a strong family health history of breast and ovarian cancer does not mean that you definitely have an inherited mutation. In fact, most women identified as being at increased risk for BRCA1 and BRCA2 mutations based on family health history do not have BRCA1 or BRCA2 mutations.

Using family health history information will not find everyone with BRCA1 or BRCA2 mutations. Not everyone with a BRCA1 or BRCA2 mutation has a strong family health history of breast and ovarian cancer. Some even have no known family health history of breast and ovarian cancer.

Circulating tumor DNA (ctDNA) is found in the bloodstream and refers to DNA that comes from cancerous cells and tumors. Most DNA is inside a cell’s nucleus. As a tumor grows, cells die and are replaced by new ones. The dead cells get broken down and their contents, including DNA, are released into the bloodstream. ctDNA are small pieces of DNA, usually comprising fewer than 200 building blocks (nucleotides) in length.

The quantity of ctDNA varies among individuals and depends on the type of tumor, its location, and for cancerous tumors, the cancer stage.

Detection of ctDNA can be helpful in the following cases:

• Detecting and diagnosing a tumor. Because tumor DNA has acquired multiple genetic mutations, leading to tumor development, ctDNA is not an exact match to the individual’s DNA. Finding DNA with genetic differences aids in tumor detection. Diagnosing the type of tumor using ctDNA can reduce the need for getting a sample of the tumor tissue (tumor biopsy), which can be challenging when a tumor is difficult to access, such as a tumor in the brain or lung.

• Guiding tumor-specific treatment. Analyzing the genome of tumor cells using ctDNA can help doctors determine which treatment will be most effective. Currently, however, approval from the U.S. Food and Drug Administration for ctDNA testing to personalize cancer treatment is limited.

• Monitoring treatment. A decrease in the quantity of ctDNA suggests the tumor is shrinking and treatment is successful.

• Monitoring periods with no symptoms (remission of cancer). A lack of ctDNA in the bloodstream indicates that the cancer has not returned.

Genomics is establishing more robust methods for DNA-based forensic analyses.

Did you know that forensic analyses of DNA were being used well before the completion of the Human Genome Project, but newer approaches are speeding up and greatly improving the process, and larger DNA databases are making searches more powerful and more widely available? The National DNA Index in the United States now contains information from over 16 million people and has been used to aid in over 387,000 investigations.

Have you ever wondered how those detectives on TV and in the movies actually use DNA analyses to match a person to a crime or to determine the identity of a person by their remains? This is how it works behind the scientific scenes. In the 0.1 percent of the human genome sequence that differs between people [see Human Genomic Variation] are a number of areas where very short stretches of DNA are repeated over and over. These regions arecalled "short tandem repeats" (or STRs). As these stretches of DNA are passed from one generation to the next, they often experience a gain or loss of one of their repeats. At a specific place in the gene TPOX, for example, there are a series of repeats of the four bases GAAT. You might have 10 copies of that GAAT in your genome, while your neighbor might have 14. Since the repeat doesn't affect whether TPOX works or not, it doesn't matter to you or your DNA how many repeats are present. But these changes from one generation to the next lead to differences among STRs across the human population. The British scientist Sir Alec Jeffreys realized in 1984 that by determining the repeat numbers at enough of these STRs across the genome, he could generate a "DNA fingerprint" that was almost unique to each individual's genome.

DNA Analysis For Human Identification

As new, more powerful technologies for amplifying and sequencing tiny amounts of DNA became available, scientists teamed up with law enforcement officials to improve the use of DNA analyses for crime solving. In the United States, the Federal Bureau of Investigation created the Combined DNA Index System (CODIS) in 1990. Today, a CODIS forensic profile combines information from analyzing 20 different STRs across the human genome. In theory, the combined data generated for this panel is specific enough to identify one person on earth.

In practice, gathering samples and accurately analyzing the DNA can be problematic. We leave our own DNA behind us all the time, through stray hairs, skin cells, or other materials. This means that samples collected from a crime scene might be a mix of multiple people, and could potentially lead to the real perpetrator of a crime to not be identified. Or, in cases of mass casualties or environmental disasters, many samples might be mixed together or subjected to high pressure, moisture, or temperature. Advances in genomic technologies, including DNA sequencing, are allowing for more precise identification, in some cases using DNA samples collected years ago. For instance, forensic scientists are still working to use DNA analyses for identifying remains from the World Trade Center site after September 11, 2001 and soldiers from the Vietnam war.

DNA forensic analyses are only as good as the people performing the tests. In some cases, samples might get mixed up in the laboratory or statistical calculations may lead to erroneous conclusions. Groups like The Innocence Project use DNA analyses to exonerate people accused of crimes by showing years later that their DNA does not match the sample(s) collected years earlier at the scene.

Finding Missing Persons with DNA Analyses

When DNA evidence is being used in missing persons case, the generated DNA profile will often include markers from mitochondrial DNA and the Y chromosome. Children only inherit mitochondrial DNA from their mother, and sons only inherit the Y chromosome from their father. One example of the use of mitochondrial DNA is the work of Dr. Mary-Claire King with the Grandmothers (Abuelas) of the Plaza de Mayo in Argentina. A group of grandmothers whose children and grandchildren were taken and given to other families donated their own DNA to help find their family members. These abuelas have been working for over 30 years; in 2014, one of the founders named Estela de Carlotto was reunited with her own grandson, marking the 114th child found through their efforts.

DNA-Based Predictions

As we improve our ability to analyze ancient DNA samples [see Human Origins and Ancestry] and to understand how our genomes encode our traits, we are gaining interesting insights about what humans looked like in the past and now. Recently, genomic analyses of a set of 10,000-year-old human remains in the United Kingdom (called "Cheddar Man" because he was found in the Cheddar Gorge), allowed scientists to predict what some of the first Britons might have looked like. According to the researchers, Cheddar Man and his relatives would have likely had dark skin, dark hair and light eyes. More recently, scientists have been working towards developing a "police sketch" based on analyses of DNA collected at a crime scene. While DNA variation cannot yet predict an exact facial appearance of a person, it can suggest some traits that can be useful for investigating a crime, like hair color and eye color. The limits of this technology have been explored in an art installation where DNA from discarded chewing gum and cigarette butts was analyzed and used to create sculptures of what the person might have looked like. While still highly speculative, forensic scientists may be able to add such an approach to their toolkit along with other lines of evidence for deducing some elements of a suspect's physical appearance.

Genetic ancestry testing, or genetic genealogy, is a way for people interested in family history (genealogy) to go beyond what they can learn from relatives or from historical documentation. Examination of DNA variations can provide clues about where a person's ancestors might have come from and about relationships between families. Certain patterns of genetic variation are often shared among people of particular backgrounds. The more closely related two individuals, families, or populations are, the more patterns of variation they typically share.

Three types of genetic ancestry testing are commonly used for genealogy:

Y chromosome testing

Variations in the Y chromosome can be used to explore ancestry in the direct male line. Only individuals with a Y chromosome (typically males) can have this type of testing done. However, people interested in this type of genetic testing sometimes recruit a relative to have the test done. Because the Y chromosome is passed on in the same pattern as are family names (surnames) in many cultures, Y chromosome testing is often used to investigate questions such as whether two families with the same surname are related.

Mitochondrial DNA testing

This type of testing identifies genetic variations in mitochondrial DNA. Although most DNA is packaged in chromosomes within the cell nucleus, cell structures called mitochondria also have a small amount of their own DNA (known as mitochondrial DNA). Both males and females have mitochondrial DNA so this type of testing can be used by either sex. Mitochondria DNA is passed on solely from egg cells so it provides information about the direct female ancestral line. Mitochondrial DNA testing can be useful for genealogy because it preserves information about female ancestors that may be lost from the historical record because of the way surnames are often passed down.

Single nucleotide polymorphism testing

These tests evaluate large numbers of individual variations (single nucleotide polymorphisms or SNPs) across a person’s entire genome. The results are compared to similar SNPs in a testing database to provide an estimate of a person's ethnic background. For example, the pattern of SNPs might indicate that a person's ancestry is approximately 50 percent African, 25 percent European, 20 percent Asian, and 5 percent unknown. (Sometimes, more regional specificity can be provided.) Genealogists use this type of test because Y chromosome and mitochondrial DNA test results, which represent only single ancestral lines, do not capture the overall ancestral background of an individual.

Genetic ancestry testing has a number of limitations. Test providers compare individuals' test results to different databases of SNPs, so ethnicity estimates may not be consistent from one provider to another. Additionally, these databases do not have equal coverage of SNPs for all ethnic populations; so results for minority populations may be nonspecific or inaccurate. Also, because most human populations have migrated many times throughout their history and mixed with nearby groups, ethnicity estimates based on genetic testing may differ from an individual's expectations. In ethnic groups with a smaller range of genetic variation due to the group's size and history, most members share many SNPs, and it may be difficult to distinguish people who have a relatively recent common ancestor, such as fourth cousins, from the group as a whole.

Genetic ancestry testing is offered by several companies and organizations. Most companies provide online forums and other services to allow people who have been tested to share and discuss their results with others, which may allow them to discover previously unknown relationships. On a larger scale, combined genetic ancestry test results from many people can be used by scientists to explore the history of populations as they arose, migrated, and mixed with other groups.

The main differences between clinical genetic testing and research testing are the purpose of the test and who receives the results. The goals of research testing include finding unknown genes, learning how genes work, developing tests for future clinical use, and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers. Clinical testing, on the other hand, is done to find out about an inherited disorder in an individual patient or family. People receive the results of a clinical test and can use them to help them make decisions about medical care or reproductive issues.

It is important for people considering genetic testing to know whether the test is available on a clinical or research basis. Clinical and research testing both involve a process of informed consent in which patients learn about the testing procedure, the risks and benefits of the test, and the potential consequences of testing.

Once a person decides to proceed with genetic testing, a health care provider can arrange testing. Genetic testing is often done as part of a genetic consultation.

Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder. The laboratory reports the test results in writing to a person's doctor or genetic counselor, or directly to the patient if requested.

Newborn screening tests are done on a small blood sample, which is taken by pricking the baby's heel. Unlike other types of genetic testing, a parent will usually only receive the result if it is positive. If the test result is positive, additional testing is needed to determine whether the baby has a genetic disorder.

Before a person has a genetic test, it is important to understand the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission is called informed consent.

Individuals interested in direct-to-consumer genetic testing do not need to go through a health care provider to obtain a test, but they can get it directly from the testing company. After undergoing direct-to-consumer genetic testing, people who test positive for a condition or are found to be at higher risk of developing a disorder are encouraged to follow-up with a genetic counselor or other health care provider.

Before a person has a genetic test, it is important that he or she fully understands the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission to carry out testing is called informed consent. "Informed" means that the person has enough information to make an educated decision about testing; "consent" refers to a person's voluntary agreement to have the test done.

In general, informed consent can only be given by adults who are competent to make medical decisions for themselves. For children and others who are unable to make their own medical decisions (such as people with impaired mental status), informed consent can be given by a parent, guardian, or other person legally responsible for making decisions on that person's behalf.

Informed consent for genetic testing is generally obtained by a doctor or genetic counselor during an office visit. The healthcare provider will discuss the test and answer any questions. If the person wishes to have the test, he or she will then usually read and sign a consent form.

Several factors are commonly included on an informed consent form:

• A general description of the test, including the purpose of the test and the condition for which the testing is being performed.
• How the test will be carried out (for example, a blood sample).
• What the test results mean, including positive and negative results, and the potential for uninformative results or incorrect results such as false positives or false negatives.
• Any physical or emotional risks associated with the test.
• Whether the results can be used for research purposes.
• Whether the results might provide information about other family members' health, including the risk of developing a particular condition or the possibility of having affected children.
• How and to whom test results will be reported and under what circumstances results can be disclosed (for example, to health insurance providers).
• What will happen to the test specimen after the test is complete.
• Acknowledgment that the person requesting testing has had the opportunity to discuss the test with a healthcare professional.
• The individual's signature, and possibly that of a witness.

The elements of informed consent may vary, because some states have laws that specify factors that must be included. (For example, some states require disclosure that the test specimen will be destroyed within a certain period of time after the test is complete.)

Informed consent is not a contract, so a person can change his or her mind at any time after giving initial consent. A person may choose not to go through with genetic testing even after the test sample has been collected. A person simply needs to notify the healthcare provider if he or she decides not to continue with the testing process.

The results of genetic tests are not always straightforward, which often makes them challenging to interpret and explain. Therefore, it is important for patients and their families to ask questions about the potential meaning of genetic test results both before and after the test is performed. When interpreting test results, health care providers consider a person’s medical history, family history, and the type of genetic test that was done.

A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic variant, identify an increased risk of developing a disease (such as cancer), or suggest a need for further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, health care providers typically cannot use a positive test result to predict the course or severity of a condition. Rarely, tests results can be false positive, which occur when results indicate an increased risk for a genetic condition when the person is unaffected.

A negative test result means that the laboratory did not find a change that is known to affect health or development in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic variant, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing, or re-testing at a later date, may be required to confirm a negative result. Rarely, tests results can be false negative, which occur when the results indicate a decreased risk or a genetic condition when the person is actually affected.

In some cases, a test result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been confirmed to play a role in the development of disease, known as a variant of uncertain significance (VUS or VOUS), it can be difficult to tell whether it is a natural polymorphism or a disease-causing variant. For these variants, there may not be enough scientific research to confirm or refute a disease association or the research may be conflicting. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result.

Secondary findings are genetic test results that provide information about changes (variants) in a gene unrelated to the primary purpose for the testing.

When a clinician orders a genetic test to discover the genetic cause of a particular condition, the test will often sequence one or a few genes that seem most likely to be associated with that individual’s set of signs and symptoms. However, if the individual’s signs and symptoms do not have an obvious genetic cause, a clinician might order a test that sequences all of the pieces of an individual's DNA that provide instructions for making proteins (called an exome) or a test that sequences all of an individual’s DNA building blocks (nucleotides), called a genome. These tests are called whole exome sequencing and whole genome sequencing, respectively.

Many more genetic changes can be identified with whole exome and whole genome sequencing than by sequencing just one or a few genes. Sometimes, testing finds a variant that is associated with a condition other than the one for which testing was originally indicated. This is called a secondary finding. Some individuals with a secondary finding may not yet have any of the symptoms associated with the condition, but may be at risk of developing it later in life. For example, a person with a variant in the BRCA1 gene, which is associated with an increased risk of breast and ovarian cancer, may not have developed cancer. Other individuals with secondary findings may have a known medical condition, such as extremely high cholesterol, but receive results that indicate a genetic cause for that condition, such as a variant in the LDLR gene.

In 2013, then again in 2017 and 2021, the American College of Medical Genetics and Genomics (ACMG) recommended that all labs performing whole exome and whole genome sequencing tests report particular secondary findings, in addition to any variants that are found related to the primary purpose of the testing. In the 2021 updated recommendations, ACMG proposed a list of 73 genes that are associated with a variety of conditions, from cancer to heart disease. The 73 genes for which secondary findings are reported were chosen because they are associated with conditions that have a definable set of clinical features, the possibility of early diagnosis, a reliable clinical genetic test, and effective intervention or treatment. The goal of reporting these secondary findings to an individual is to provide medical benefit by preventing or better managing health conditions. The variants that are reported are known to cause disease. Variants of unknown significance, whose involvement in disease at the current time is unclear, are not reported.

The information provided by secondary findings can be very important because it may help prevent a disease from occurring or guide the management of signs and symptoms if the disease develops or is already present. However, as with any type of medical diagnosis, the news of an unexpected potential health problem may lead to additional health costs and stress for individuals and their families. On the basis of secondary findings, additional testing to confirm results, ongoing screening tests, or preventive care may be advised. Individuals receiving whole exome or whole genome sequencing can choose to “opt out” of analysis of the 73 secondary finding genes and not receive variant results. As whole exome and whole genome sequencing become more common, it is important for individuals to understand what type of information they may learn and how it can impact their medical care.

Before undergoing genetic testing, it is important to be sure that the test is valid and useful. A genetic test is valid if it provides an accurate result. Two main measures of accuracy apply to genetic tests: analytical validity and clinical validity. Another measure of the quality of a genetic test is its usefulness, or clinical utility.

• Analytical validity refers to how well the test predicts the presence or absence of a particular gene or genetic change. In other words, can the test accurately detect whether a specific genetic variant is present or absent?

• Clinical validity refers to how well the genetic variant being analyzed is related to the presence, absence, or risk of a specific disease.

• Clinical utility refers to whether the test can provide helpful information about diagnosis, treatment, management, or prevention of a disease.

All laboratories that perform health-related testing, including genetic testing, are subject to federal regulatory standards called the Clinical Laboratory Improvement Amendments (CLIA) or even stricter state requirements. CLIA standards cover how tests are performed, the qualifications of laboratory personnel, and quality control and testing procedures for each laboratory. By controlling the quality of laboratory practices, CLIA standards are designed to ensure the analytical validity of genetic tests.

CLIA standards do not address the clinical validity or clinical utility of genetic tests. The Food and Drug Administration (FDA) requires information about clinical validity for some genetic tests, particularly those tests that have been produced by a lab (known as laboratory-developed tests). Additionally, states may require additional information on clinical validity for laboratory tests performed for people living in that state. Test takers, health care providers, and health insurance companies are often the ones who determine the clinical utility of a genetic test.

It can be difficult to determine the quality of a genetic test sold directly to the public. Some providers of direct-to-consumer genetic tests are not CLIA-certified, so it can be difficult to tell whether their tests are valid. If providers of direct-to-consumer genetic tests offer easy-to-understand information about the scientific basis of their tests, it can help people make more informed decisions. It may also be helpful to discuss any concerns with a health care providers before ordering a direct-to-consumer genetic test and after receiving test results.

Genetic testing has potential benefits whether the results are positive or negative for a gene mutation. Test results can provide a sense of relief from uncertainty and help people make informed decisions about managing their health care. For example, a negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available prevention, monitoring, and treatment options. Some test results can also help people make decisions about having children. Newborn screening can identify genetic disorders early in life so treatment can be started as early as possible.

The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a method that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus.

Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern. (Refer to What is genetic discrimination? for additional information.)

Genetic testing can provide only limited information about an inherited condition. The test often can't determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed.

A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision.

Genetic discrimination occurs when people are treated differently by their employer or insurance company because they have a gene mutation that causes or increases the risk of an inherited disorder. Fear of discrimination is a common concern among people considering genetic testing.

Several laws at the federal and state levels help protect people against genetic discrimination. In particular, a federal law called the Genetic Information Nondiscrimination Act (GINA) is designed to protect people from this form of discrimination.

GINA has two parts: Title I, which prohibits genetic discrimination in health insurance, and Title II, which prohibits genetic discrimination in employment. Title I makes it illegal for health insurance providers to use or require genetic information to make decisions about a person's insurance eligibility or coverage. This part of the law went into effect on May 21, 2009. Title II makes it illegal for employers to use a person's genetic information when making decisions about hiring, promotion, and several other terms of employment. This part of the law went into effect on November 21, 2009.

GINA and other laws do not protect people from genetic discrimination in every circumstance. For example, GINA does not apply when an employer has fewer than 15 employees. It does not cover people in the U.S. military or those receiving health benefits through the Veterans Health Administration or Indian Health Service. GINA also does not protect against genetic discrimination in forms of insurance other than health insurance, such as life, disability, or long-term care insurance.

Screening tests evaluate an individual’s risk of developing a genetic condition, while diagnostic tests identify genetic conditions. All genetic tests have both benefits and limitations.

Genetic screening tests are generally used in people who do not have signs or symptoms of a disorder. These tests estimate whether an individual’s risk of having a certain condition is increased or decreased compared with the risk in other people in a similar population. A positive result means that a person’s risk of developing the condition is higher than average. A negative screening test means that a person’s risk is lower than average. However, having a positive screening result does not mean the individual has the condition. Because screening tests are only estimates, in some cases the results indicate an increased risk for a genetic abnormality when the person is actually unaffected (false positive), or the results indicate a decreased risk for a genetic abnormality when the person is really affected (false negative). While genetic screening tests do not provide a conclusive answer, they can help guide next steps, such as whether additional, diagnostic testing is needed.

Genetic diagnostic tests are often used in people who have signs and symptoms. These tests are used to confirm or rule out suspected genetic conditions. Diagnostic tests can also help inform a person’s chance of developing a genetic condition or of passing on a genetic condition to their children. Diagnostic testing can be performed before birth or at any time during a person's life, but it is not available for all genes or all genetic conditions. The results of a diagnostic test can be used to guide a person's choices about health care and the management of the disorder.

Examples of genetic screening tests include:

Noninvasive prenatal testing/screening (NIPT/NIPS): This screening test is performed before birth to help determine the risk that a fetus will be born with certain genetic abnormalities, such as Down syndrome and other chromosomal disorders.

Newborn screening: In the United States, a screening test is performed on all newborns shortly after birth. This test can assess the risk for developing more than 35 genetic conditions. For many of these conditions, the test analyzes various protein and enzyme levels, which would be abnormal in affected individuals.

Examples of genetic diagnostic tests include:

Molecular gene tests: These tests determine the order of DNA building blocks (nucleotides) in an individual's genetic code, a process called DNA sequencing. The purpose of these tests is to identify genetic changes that can cause disease.

Chromosomal tests: These tests analyze whole chromosomes or long lengths of DNA to identify large-scale changes, such as an extra or missing copy of a chromosome (trisomy or monosomy, respectively) or abnormalities of large segments of chromosomes, that underlie certain genetic conditions.

Most of the time, genetic testing is done through healthcare providers such as physicians, nurse practitioners, and genetic counselors. Healthcare providers determine which test is needed, order the test from a laboratory, collect and send the DNA sample, interpret the test results, and share the results with the patient. Often, a health insurance company covers part or all of the cost of testing.

Direct-to-consumer genetic testing is different: these genetic tests are marketed directly to customers via television, print advertisements, or the Internet, and the tests can be bought online or in stores. Customers send the company a DNA sample and receive their results directly from a secure website or in a written report. Direct-to-consumer genetic testing provides people access to their genetic information without necessarily involving a healthcare provider or health insurance company in the process.

Dozens of companies currently offer direct-to-consumer genetic tests for a variety of purposes. The most popular tests use genetic variations to make predictions about health, provide information about common traits, and offer clues about a person’s ancestry. The number of companies providing direct-to-consumer genetic testing is growing, along with the range of health conditions and traits covered by these tests. Because there is currently little regulation of direct-to-consumer genetic testing services, it is important to assess the quality of available services before pursuing any testing.

Other names for direct-to-consumer genetic testing include DTC genetic testing, direct-access genetic testing, at-home genetic testing, and home DNA testing. Ancestry testing (also called genealogy testing) is also considered a form of direct-to-consumer genetic testing.

The cost of genetic testing can range from under $100 to more than $2,000, depending on the nature and complexity of the test. The cost increases if more than one test is necessary or if multiple family members must be tested to obtain a meaningful result. For newborn screening, costs vary by state. Some states cover part of the total cost, but most charge a fee of $15 to $60 per infant.

From the date that a sample is taken, it may take a few weeks to several months to receive the test results. Results for prenatal testing are usually available more quickly because time is an important consideration in making decisions about a pregnancy. The doctor or genetic counselor who orders a particular test can provide specific information about the cost and time frame associated with that test.

In many cases, health insurance plans will cover the costs of genetic testing when it is recommended by a person's doctor. Health insurance providers have different policies about which tests are covered, however. A person interested in submitting the costs of testing may wish to contact his or her insurance company beforehand to ask about coverage.

Some people may choose not to use their insurance to pay for testing because the results of a genetic test can affect a person's insurance coverage. Instead, they may opt to pay out-of-pocket for the test. People considering genetic testing may want to find out more about their state's privacy protection laws before they ask their insurance company to cover the costs.

Determining the order of DNA building blocks (nucleotides) in an individual's genetic code, called DNA sequencing, has advanced the study of genetics and is one technique used to test for genetic disorders. Two methods, whole exome sequencing and whole genome sequencing, are increasingly used in healthcare and research to identify genetic variations; both methods rely on new technologies that allow rapid sequencing of large amounts of DNA. These approaches are known as next-generation sequencing (or next-gen sequencing).

The original sequencing technology, called Sanger sequencing (named after the scientist who developed it, Frederick Sanger), was a breakthrough that helped scientists determine the human genetic code, but it is time-consuming and expensive. The Sanger method has been automated to make it faster and is still used in laboratories today to sequence short pieces of DNA, but it would take years to sequence all of a person's DNA (known as the person's genome). Next-generation sequencing has sped up the process (taking only days to weeks to sequence a human genome) while reducing the cost.

With next-generation sequencing, it is now feasible to sequence large amounts of DNA, for instance all the pieces of an individual's DNA that provide instructions for making proteins. These pieces, called exons, are thought to make up 1 percent of a person's genome. Together, all the exons in a genome are known as the exome, and the method of sequencing them is known as whole exome sequencing. This method allows variations in the protein-coding region of any gene to be identified, rather than in only a select few genes. Because most known mutations that cause disease occur in exons, whole exome sequencing is thought to be an efficient method to identify possible disease-causing mutations.

However, researchers have found that DNA variations outside the exons can affect gene activity and protein production and lead to genetic disorders--variations that whole exome sequencing would miss. Another method, called whole genome sequencing, determines the order of all the nucleotides in an individual's DNA and can determine variations in any part of the genome.

While many more genetic changes can be identified with whole exome and whole genome sequencing than with select gene sequencing, the significance of much of this information is unknown. Because not all genetic changes affect health, it is difficult to know whether identified variants are involved in the condition of interest. Sometimes, an identified variant is associated with a different genetic disorder that has not yet been diagnosed (these are called incidental or secondary findings).

In addition to being used in the clinic, whole exome and whole genome sequencing are valuable methods for researchers. Continued study of exome and genome sequences can help determine whether new genetic variations are associated with health conditions, which will aid disease diagnosis in the future.

Do you know what the slogan "it's in your DNA" is really all about? Our ever improving ability to read anyone's genome sequence raises many issues regarding the social context of genomics. Information about our genomes is starting to become part of our everyday life. Genomic information shapes societal messages about DNA in how we think about ourselves and how others view us.

Companies, universities, nonprofits, and many other organizations have used the slogan "it's in our DNA" to mean that something is part of their core mission or values. Our understanding of our DNA also extends to our understanding of ourselves: what is in your DNA? Is it the chin that looks like your mother's or the eye color that is just like your grandfather's? What story does your DNA tell about the hundreds or thousands of ancestors before you? What continents did they migrate through in times long past? How does your DNA contribute to who you are, or how you are treated within your society?

Continued studies of the ethical, legal, and social implications of genomic advances can help to break down barriers and yield a better appreciation of what truly is, and is not, in our DNA - and what that means to us, our families, and communities and society.

Ethical and Social Questions

The scientists who launched the Human Genome Project recognized immediately that having a complete human genome sequence would raise many ethical and social issues. In 1990, the Ethical, Legal, and Social Implications (ELSI) Research Program was formally established at the National Institutes of Health (NIH) as an integral part of the Human Genome Project. The research supported by this program, ranges from genomics and health disparities to inclusion of diverse populations in genomics research, to whether people should have the right to refuse to know genomic testing results. Over the last 15 years, this research has greatly advanced our understanding and appreciation of the complex societal implications of genomics.

Consent and Privacy

Among the major areas of study in ELSI research are questions about consent and privacy. For example, what do you need to know about a research study that will use your DNA before you agree to participate? That's called "informed consent." As new areas of genomics have developed in recent years (like learning about microbiomes), researchers have needed to continually update their guidelines, so as to help people understand the relevant risks and benefits before signing up to be a research participant. Such studies are overseen by Institutional Review Boards (or IRBs), and these boards are made up of scientists, ethicists, and members of the community. An IRB must approve any research projects involving humans.

The widespread availability of genomic data has brought changes to privacy considerations as well. When a test is performed on your DNA, either through a research or clinical program, how is the privacy of your genomic data maintained and does that align with how you want those data to be protected? Since you share half of your genome with each of your parents, and half with each of your children, the information is not just about your genome. Should you be able to stop your relatives from revealing genomic information that could be relevant to you as well? And does that answer change based on what the test is for? Let's say that one of your parents learns from a genetic test that they have Huntington's disease, which is often diagnosed quite late in life. This gives you a 50-50 chance of carrying the same genetic mutation for this fatal neurological disease. Some people react to such information by wanting to know right away what their future might be, while others do not want to know.

Another privacy issue that has arisen in the genomics era is when are you entitled to receive all of your data back from a DNA-based research study or a clinical test. In the case of genomic tests, this can often be a lot of data! Research studies do not often return data to their participants, whereas patients are more often provided the results of clinical tests. If you have had direct-to-consumer (or DTC) genomic testing, the companies might have let you download your entire dataset. You might want to share such data with other research groups in order to further science or with other healthcare professionals for your medical care. There are also many questions about what the companies might do with the data, and most companies have user agreements which you must agree to, where they specify their plans up front. This may include sharing your data with others, including pharmaceutical companies and law enforcement. As President Obama noted in 2016, there is a difficult balance in making your data available for some purposes while still keeping them private for other reasons.

Discrimination

Concerns also exist about potential discrimination based on information about a person's DNA. In 2008, President Bush signed into law the Genetic Information Nondiscrimination Act (or GINA for short). This law is now enforced by multiple federal agencies, including the United States Equal Employment Opportunity Commission. You might have seen posters saying, "Equal Employment Opportunity is THE LAW" - those posters point out that GINA now specifically protects job applicants and current employees from discrimination based on their genetic information. GINA also prohibits health insurers from discriminating against anyone based on their genetic information when determining coverage or rates. At this time, GINA does not cover life insurance, disability insurance, or long-term care insurance. As in all potential discrimination areas, even though legal protections are in place under GINA, it is important to be knowledgeable about your rights and to know if and when they might be abused.

Race

The broad availability of genomic ancestry testing is influencing the way we think about the concept of race in America (see Human Origins and Ancestry). We now understand that skin color, as one component of how we think of ourselves, is due to a complex interaction of genes and the environment (see Human Genomic Variation). When we can see the genomic patterns of our ancestors in our own DNA, it might not be the same as how we describe ourselves (or how they described themselves). Large studies of African Americans in the United States have shown that their genomes contain an average of 25 percent European DNA sequences; in the same studies, Latino genomes in the United States show a mix of DNA from African, Native American, and European sources. It turns out that two people who call themselves the same race may be quite different at the genomic level. With our emerging understanding of genomics, we can combine genomic information with historical records and social data in order to study the shaping of concepts such as race.

Other characteristics often associated with race are part of culture but are not written in our DNA. Racial terms change over time, sometimes even multiple times within one person's life. For example, the categories used by the national census in the United States have also contributed to what we think of as "race," but they have changed quite substantially over time. The term "Hispanic" was not offered as a way that a person could describe themselves until the 1970 census, but by 2010, people could answer whether they were "of Hispanic, Latino, or Spanish origin." Genomics is helping us understand the complex and intertwined relationships between a person's or groups' ancestry, ethnicity, and racial identity. The National Human Genome Research Institute is also monitoring the use of race and ethnicity in biomedical research, including any influence on health disparities and inclusion/engagement of underrepresented populations in genomics.

A gene patent is the exclusive rights to a specific sequence of DNA (a gene) given by a government to the individual, organization, or corporation who claims to have first identified the gene. Once granted a gene patent, the holder of the patent dictates how the gene can be used, in both commercial settings, such as clinical genetic testing, and in noncommercial settings, including research, for 20 years from the date of the patent. Gene patents have often resulted in companies having sole ownership of genetic testing for patented genes.

On June 13, 2013, in the case of the Association for Molecular Pathology v. Myriad Genetics, Inc., the Supreme Court of the United States ruled that human genes cannot be patented in the U.S. because DNA is a "product of nature." The Court decided that because nothing new is created when discovering a gene, there is no intellectual property to protect, so patents cannot be granted. Prior to this ruling, more than 4,300 human genes were patented. The Supreme Court's decision invalidated those gene patents, making the genes accessible for research and for commercial genetic testing.

The Supreme Court's ruling did allow that DNA manipulated in a lab is eligible to be patented because DNA sequences altered by humans are not found in nature. The Court specifically mentioned the ability to patent a type of DNA known as complementary DNA (cDNA). This synthetic DNA is produced from the molecule that serves as the instructions for making proteins (called messenger RNA).

Noninvasive prenatal testing (NIPT), sometimes called noninvasive prenatal screening (NIPS), is a method of determining the risk that the fetus will be born with certain genetic abnormalities. This testing analyzes small fragments of DNA that are circulating in a pregnant woman’s blood. Unlike most DNA, which is found inside a cell’s nucleus, these fragments are free-floating and not within cells, and so are called cell-free DNA (cfDNA). These small fragments usually contain fewer than 200 DNA building blocks (base pairs) and arise when cells die off and get broken down and their contents, including DNA, are released into the bloodstream.

During pregnancy, the mother’s bloodstream contains a mix of cfDNA that comes from her cells and cells from the placenta. The placenta is tissue in the uterus that links the fetus and the mother’s blood supply. These cells are shed into the mother’s bloodstream throughout pregnancy. The DNA in placental cells is usually identical to the DNA of the fetus. Analyzing cfDNA from the placenta provides an opportunity for early detection of certain genetic abnormalities without harming the fetus.

NIPT is most often used to look for chromosomal disorders that are caused by the presence of an extra or missing copy (aneuploidy) of a chromosome. NIPT primarily looks for Down syndrome (trisomy 21, caused by an extra chromosome 21), trisomy 18 (caused by an extra chromosome 18), trisomy 13 (caused by an extra chromosome 13), and extra or missing copies of the X chromosome and Y chromosome (the sex chromosomes). The accuracy of the test varies by disorder.

NIPT may include screening for additional chromosomal disorders that are caused by missing (deleted) or copied (duplicated) sections of a chromosome. NIPT is beginning to be used to test for genetic disorders that are caused by changes (variants) in single genes. As technology improves and the cost of genetic testing decreases, researchers expect that NIPT will become available for many more genetic conditions.

NIPT is considered noninvasive because it requires drawing blood only from the pregnant woman and does not pose any risk to the fetus. NIPT is a screening test, which means that it will not give a definitive answer about whether or not a fetus has a genetic condition. The test can only estimate whether the risk of having certain conditions is increased or decreased. In some cases, NIPT results indicate an increased risk for a genetic abnormality when the fetus is actually unaffected (false positive), or the results indicate a decreased risk for a genetic abnormality when the fetus is actually affected (false negative). Because NIPT analyzes both fetal and maternal cfDNA, the test may detect a genetic condition in the mother.

There must be enough fetal cfDNA in the mother’s bloodstream to be able to identify fetal chromosome abnormalities. The proportion of cfDNA in maternal blood that comes from the placenta is known as the fetal fraction. Generally, the fetal fraction must be above 4 percent, which typically occurs around the tenth week of pregnancy. Low fetal fractions can lead to an inability to perform the test or a false negative result. Reasons for low fetal fractions include testing too early in the pregnancy, sampling errors, maternal obesity, and fetal abnormality.

There are multiple NIPT methods to analyze fetal cfDNA. To determine chromosomal aneuploidy, the most common method is to count all cfDNA fragments (both fetal and maternal). If the percentage of cfDNA fragments from each chromosome is as expected, then the fetus has a decreased risk of having a chromosomal condition (negative test result). If the percentage of cfDNA fragments from a particular chromosome is more than expected, then the fetus has an increased likelihood of having a trisomy condition (positive test result). A positive screening result indicates that further testing (called diagnostic testing, because it is used to diagnose a disease) should be performed to confirm the result.

Before undergoing genetic testing, it is important to be sure that the test is valid and useful. A genetic test is valid if it provides an accurate result. Two main measures of accuracy apply to genetic tests: analytical validity and clinical validity. Another measure of the quality of a genetic test is its usefulness, or clinical utility.

• Analytical validity refers to how well the test predicts the presence or absence of a particular gene or genetic change. In other words, can the test accurately detect whether a specific genetic variant is present or absent?

• Clinical validity refers to how well the genetic variant being analyzed is related to the presence, absence, or risk of a specific disease.

• Clinical utility refers to whether the test can provide information about diagnosis, treatment, management, or prevention of a disease that will be helpful to a consumer.

All laboratories that perform health-related testing, including genetic testing, are subject to federal regulatory standards called the Clinical Laboratory Improvement Amendments (CLIA) or even stricter state requirements. CLIA standards cover how tests are performed, the qualifications of laboratory personnel, and quality control and testing procedures for each laboratory. By controlling the quality of laboratory practices, CLIA standards are designed to ensure the analytical validity of genetic tests.

CLIA standards do not address the clinical validity or clinical utility of genetic tests. The Food and Drug Administration (FDA) requires information about clinical validity for some genetic tests. Additionally, the state of New York requires information on clinical validity for all laboratory tests performed for people living in that state. Consumers, health providers, and health insurance companies are often the ones who determine the clinical utility of a genetic test.

It can be difficult to determine the quality of a genetic test sold directly to the public. Some providers of direct-to-consumer genetic tests are not CLIA-certified, so it can be difficult to tell whether their tests are valid. If providers of direct-to-consumer genetic tests offer easy-to-understand information about the scientific basis of their tests, it can help consumers make more informed decisions. It may also be helpful to discuss any concerns with a health professional before ordering a direct-to-consumer genetic test.

As the field of genomics advances, genetic and genomic tests are becoming more common in, and out of, the clinic. Yet most genetic tests today are not regulated, meaning that they go to market without any independent analysis to verify the claims of the seller.

Federal Regulation

Several federal agencies regulate genetic tests: the Food and Drug Administration (FDA), the Centers for Medicare and Medicaid Services (CMS), and the Federal Trade Commission (FTC).

Genetic and Genomic tests, like other types of diagnostic tests, can be evaluated and regulated on the following three criteria, adapted from the National Library of Medicine's Genetics Home Reference.

Analytical Validity: Refers to how well the test predicts the presence or absence of a particular gene or genetic change. Can the test consistently and accurately detect whether a specific genetic variant is present or absent?

Clinical Validity: Refers to how well the genetic variant(s) being analyzed is related to the presence, absence, or risk of a specific disease. Has having a specific genetic variant been conclusively shown to increase the risk or likelihood of having a disease or eventually developing a disease?

Clinical Utility: Refers to whether the test can provide information about diagnosis, treatment, management, or prevention of a disease that will be helpful to patients and their providers. Will use of the test lead to improved health outcomes

CMS implements regulations to control the analytical validity of clinical genetic tests, but there is no federal oversight of the clinical validity of most genetic tests. In light of this, FDA has proposed new policies to enhance analytical validity regulation and expand oversight of the clinical validity of genetic tests. Neither agency has issued formal plans to regulate the clinical utility of genetic tests, but typically, health care insurers like CMS draw on data from the research and medical communities to determine the clinical utility of medical treatments and procedures. Since clinical genomics is a relatively new field, frameworks to evaluate the clinical utility of genetic tests are still being developed. With time and experience, researchers, clinicians, health insurance companies, and regulators will have better information with which to establish the clinical utility of genetic tests.

CMS Regulation

CMS regulates clinical laboratories, including laboratories conducting clinical genetic testing, through its CLIA program. CLIA refers to the "Clinical Laboratory Improvement Amendments" of 1988, which established a certification process laboratories must pass in order to legally conduct clinical testing. The objective of CLIA is to determine clinical testing quality, including verification of the procedures used and the qualifications of the technicians processing the tests. It also comprises proficiency testing for some tests.

Though CLIA does look at the analytical validity of genetic tests, it does not examine whether the tests performed are clinically valid. Since the 1990s, expert panels and members of Congress have expressed concern about this regulatory gap and the need for FDA to address it. In response, in 2010 the FDA announced plans to move away from a policy of "enforcement discretion" (see next section, "FDA Regulation", for an explanation of the term "enforcement discretion") and expand its regulation to all genetic tests; this expansion has yet to take place due to the complexity of the task at hand.

FDA Regulation

Part of the FDA's mission is to protect public health by ensuring the safety, efficacy, and security of drugs, biological products, and medical devices. The agency considers genetic tests to be a special type of medical device, and therefore these diagnostic tools fall within FDA's regulatory purview. Until recent years, FDA chose to apply "enforcement discretion" to the vast majority of genetic tests. The FDA can use "enforcement discretion" when it has the authority to regulate tests but chooses not to. In the current regulatory landscape, whether FDA regulates a test is determined by how it comes to market. A test may be marketed as a commercial test "kit," a group of reagents used in the processing of genetic samples that are packaged together and sold to multiple labs. Test kit manufacturers must receive approval from FDA before selling their products on the market. More commonly, a test comes to market as a laboratory-developed test (LDT), where the test is developed and performed by a single laboratory, and where specimen samples are sent to that laboratory to be tested. To date, FDA has practiced enforcement discretion for LDTs. This means that LDTs are being used in the clinic without the FDA's assessment of their analytical and clinical validity.

FDA initially applied enforcement discretion on LDTs T because clinical genetic testing was not very widespread in the past - however, due to the rapid advances in next-generation sequencing (NGS) technology, the pervasiveness of clinical genetic testing today, the growth of direct-to-consumer (DTC) genomic testing, and FDA's mounting concern that unregulated tests pose a public health threat, FDA is modifying its approach. To this end, FDA has drafted new guidance to describe how it intends to regulate NGS genetic tests and verify their analytical and clinical validity. The agency has also drafted guidance proposing a new regulatory framework for LDTs. FDA "guidance" is different from laws and regulation in that it only represents the FDA's "current thinking" on a topic and is not legally binding for FDA or the parties it regulates. In practice, however, adhering to FDA guidance is beneficial because it can streamline the regulatory process.