The human body is made of trillions of cells, each specialized to perform a particular function. Inside each of these cells is a nucleus, which contains chromosomes—the structures that hold genes. Normally, each individual has 46 chromosomes arranged into 23 pairs. Half of an individual’s chromosomes are inherited from his or her mother in the egg and the other half are inherited from his or her father in the sperm. Chromosomes can be thought of as packages of tightly wound string that hold genetic information. Each chromosome has anywhere from a few hundred to a few thousand genes, with approximately 20,000 genes total. All genetic information is made up of deoxyribonucleic acid, or DNA. DNA consists of four types of nucleotides, building blocks that correspond with letters of the alphabet: A, C, T, and G. An individual gene may contain anywhere from a few hundred to several thousand of these letters. A complete sequence of billions of these letters determines an individual’s genetic code. Differences in the order, number, and/or type of these letters are all examples of genetic changes, or variants. This entire set of billions of DNA letters within an individual is known as the genome.

Not all of the DNA in the genome is directly part of specific genes. In fact, protein-coding (instruction-delivering) sequences only make up about 1-2% of the human genome. This subset of the genome is called the exome. Although the exome is a small part of the entire genome, currently it is the part most well-understood by scientists studying the genomic sequence changes involved in human disease. Just like whole genome sequencing, whole exome sequencing is available as a clinical genetic test that physicians may order for their patients. Instead of sequencing, or spelling out, each of the 3 billion letters as in a whole genome sequencing test, exome sequencing spells out only the 1-2% of the genome directly providing instructions to the cells of the body. Whole exome sequencing can provide a great deal of clinical information to a physician. However, whole genome sequencing often provides a better look at the exome than whole exome sequencing alone. Additionally, variants have been discovered outside of the exome that are thought to impact the function of the gene(s) nearby. As more patients receive whole genome sequencing, the understanding of the human health implications of these variants is likely to increase, improving the chance that whole genome sequencing is able to provide a clinical diagnosis.

A genetic disorder called albinism is one example that can be used to explain the terms “mutation” and “variant.” Albinism is a medical condition in which the body is unable to make melanin, a substance that gives color to hair, skin, and the iris of the eye. Mutations in the OCA2 gene cause one form of albinism. Individuals with this type of albinism have white or very light-colored hair, white skin, pink appearance to their irises, vision problems, and an increased risk to develop skin cancer. When both copies of the OCA2 gene have a mutation, that individual has albinism. Yet not all changes in the OCA2 gene cause albinism. Some changes in the OCA2 gene result in blue eyes, with no associated health problems. It may make sense to call a change that results in a medical condition a mutation, but it does not make sense to use this term to describe a gene change that does not result in a difference in health. To simplify this, all gene changes—whether or not they are known to cause a medical condition—are now referred to as variants.

In 2008, a federal law known as the Genetic Information Nondiscrimination Act (GINA) went into effect to help prevent genetic discrimination. GINA prohibits health insurance companies from using genetic information to determine whether someone is eligible for coverage or to determine his or her policy premium. Additionally, health insurance companies cannot ask or require patients to undergo genetic testing. This act also prevents many employers from discriminating against an employee or prospective hire based on genetic information. GINA does not prevent all types of discrimination, however. For companies with fewer than 15 employees, these employment protections do not apply. GINA’s protections do not apply to the US military or to federal government employees. Additionally, life, disability, and long-term care insurance policies are not included among GINA’s protections. These groups may still continue to use genetic information to determine one’s eligibility for coverage and/or policy premiums. Because of these important exceptions, an individual considering any type of genetic testing (clinically or as part of a research study) should discuss the possibility of genetic discrimination with his or her physician or genetic counselor. To learn more, visit http://www.ginahelp.org.

For patients and families that have an unusual medical condition, the search for a diagnosis can go on for many years. During this “diagnostic odyssey,” physicians and families will try many different treatments while a diagnosis is sought. For those individuals with an undiagnosed genetic disorder, whole genome sequencing can be undertaken to establish a diagnosis. Experience now shows that this test can find an answer in about 25% of cases, even after an extensive work-up has failed. The diagnosis of a genetic disorder does not always lead to a treatment. Nevertheless, it can be very useful. Knowing the genetic basis for a disorder allows physicians to compare the patient’s clinical course to that of other individuals with the same disorder. The doctor can sometimes better predict patient outcomes and anticipate future needs for support services and advanced care. Additionally, a diagnosis is the first step to finding effective treatment when none exist. Researchers and pharmaceutical companies need this information in order to develop treatments. A diagnosis can give families peace of mind that they now understand what is causing a patient’s problems. When physicians find an answer, they can stop the ongoing search—saving money and avoiding further tests that may be dangerous.

The Genetic and Rare Diseases Information Center (GARD) provides access to current, reliable, and easy to understand information about genetic and rare diseases in English and Spanish. Source: Office of Rare Diseases Research & the Genetic and Rare Diseases Information Center http://rarediseases.info.nih.gov/gard

Information on genetic disorders in general and a listing of resources where further information can be found Source: MedlinePlus http://www.nlm.nih.gov/medlineplus/geneticdisorders.html