Preimplantation genetic diagnosis (PGD) is a procedure used to identify genetic or chromosomal abnormalities in developing oocytes or embryos during a cycle of in vitro fertilization (IVF). Preimplantation genetic diagnosis was first introduced in the late 1980s as a viable alternative to prenatal diagnosis that would assist couples in avoiding pregnancy terminations due to fatal or debilitating diseases when one or both parents are affected by specific genetic abnormalities. Since that time, technological advances in biopsy methods and genetic analysis have improved the accuracy of the techniques and contributed to an expanding list of indications for its use.

Common indications for PGD include Huntington disease, hemophilia, and cystic fibrosis. Studies have also indicated that PGD may help select good-quality embryos and improve infertile couples’ chances to conceive and deliver a healthy baby, especially among women of advanced age, or with previous IVF failure or recurrent pregnancy loss.

Today there are a number of genetic tests that can be used to inform a couple about the possible outcomes of a current or future pregnancy. Examples of two such tests are prenatal diagnosis and preimplantation genetic diagnosis (PGD). Prenatal diagnosis can be used to diagnose a condition in a developing fetus. Today, doctors are able to diagnose many more birth defects than they are able to treat before birth. If a fetus has a condition for which prenatal treatment is not possible, prenatal diagnosis may help parents prepare emotionally for the birth and to plan the delivery with their health care providers. Parents can also use this information to make decisions regarding whether or not to continue the pregnancy.

PGD represents an alternative to prenatal diagnosis. It is used following in vitro fertilization to diagnose a genetic disease or condition in embryos. Only embryos that do not carry the disease-causing mutation are implanted in the mother's womb. PGD allows testing to occur before a pregnancy begins.

In many cases, the disease-causing mutation must be identified in an affected relative before PGD or prenatal diagnosis can be performed.

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.

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.