What is rare disease?

A genetic health condition is a condition that is caused by a variant or change in someone’s genes. The gene is considered the basic unit of inheritance. The genome is the entire set of DNA instructions found in a cell - these instructions are present in all cells of the body and are passed on from parents to offspring. Some genetic changes or variants can be new in a child (de novo) that were not inherited from or present in their parent(s). Genes code for specific proteins, or segments of proteins, which have differing functions within the body. Humans have approximately 20,000 protein-coding genes.

Mendelian inheritance refers to certain patterns of how traits are passed from parents to offspring. These general patterns were established by the Austrian monk Gregor Mendel, who performed thousands of experiments with pea plants in the 19th century. Mendel’s discoveries of how traits (such as color and shape) are passed down from one generation to the next introduced the concept of inheritance.

A rare genetic disease is defined as a condition that impacts fewer than 200,000 people in the U.S. There are more than 10,000 known rare diseases that affect about 1 in 10 people (or 30 million people) in the U.S. Other countries may have their own official definitions of a rare disease. For example, the European Union defines a disease as rare when it affects fewer than 1 in 2,000 people.

Some rare diseases are genetic and run in families and are inherited from one generation to the next. A condition that is “familial” is one that runs in families and may have an identifiable genomic variation that is present in each of the affected members of the family, and is not present in the unaffected members of the family. Rare genetic disease can also be sporadic or new in an individual and not inherited from a parent, with no other family members who are affected.  Within the rare disease category, an undiagnosed disease is a medical condition without a known cause despite a lot of evaluation. Some undiagnosed diseases remain undiagnosed because the genetic cause has not been identified or there are not yet enough cases identified to be certain that a specific gene or gene variant causes disease. The undiagnosed disease may be complex and caused by many genes working together, or due to interactions between one or more genes and environmental exposures. Or the condition may be caused by something non-genetic, such as an injury or environmental exposure.

For some individuals, a diagnosis can be found relatively quickly. For others it may take many months or years, or a diagnosis may never be found. For example, some babies are given a genetic diagnosis after having newborn screening, a form of genetic testing that all babies in the U.S. have to screen for serious health conditions that can impact young children. Some children receive a genetic diagnosis when genetic testing is done after they first show symptoms or developmental differences. Many adults are living with undiagnosed diseases, despite having genetic testing. The process of finding a diagnosis is sometimes referred to as a diagnostic odyssey. 

There are a few options if a diagnosis cannot be made. Re-analysis of genetic data every few years is one way to re-evaluate a genetic test. New clinical genetic tests may become available as new technologies are developed over time. Individuals can also enroll in research studies in which researchers plan to return results to participants and are using and developing research tests that are not yet be available in a typical medical setting. Patients can enquire with their medical and insurance providers about whether some or all of these options are available to them.

Genetic testing is the use of a clinical test to examine an individual’s DNA. There are many types of genetic tests including tests designed to look for large changes impacting many genes, as well as genetic tests designed to detect small changes or variations within genes.

In a medical setting, the results of a genetic test can be used to confirm or rule out a suspected genetic disease. Results may also be used to determine the likelihood of parents passing on a genetic mutation to their children - in this case, the parents of the affected individual or those considering having children are tested. For a child, genetic testing can be performed prenatally or after birth.

Results from genetic testing are often not black and white for rare genetic diseases. For some, a genetic test result may find a genetic variant that is the cause of a genetic condition (a pathogenic or “positive” result). For others, it may not find any genetic variants that explain the symptoms (a benign or “negative” result). Testing can also find a genetic variant for which we do not yet know if or how this variant may impact health (variant of uncertain significance or VUS). Genetic testing can also reveal information that is unexpected or unrelated to the initial purpose for doing the genetic test (sometimes called “incidental” or “secondary” findings).

People with a rare disease diagnosis, individuals with undiagnosed disease, and families and caregivers have unique experiences. They may encounter obstacles as they look for and adapt to a diagnosis and advocate for their medical, social, and psychological well-being. Many rare and undiagnosed disease families have shared their own stories and have created patient advocacy groups to help provide community and support for others.

The GREGoR Consortium does not provide clinical advice, clinical genetic testing, or direct support to patients. If you or a family member or someone you care for has a rare disease, there are local, national, and international resources that may be helpful. Some of these include:

• GeneReviews
• Genetic Alliance
• Genetic and Rare Disease Information Center
• Global Genes
• MedlinePlus Genetics - Help Me Understand Genetics page
• National Organization for Rare Disorders
• Rare Disease Day
• Undiagnosed Diseases Network
• Undiagnosed Diseases Network Foundation

For more information about how to get clinical genetic testing or to have an evaluation by a genetics professional, you can speak with your healthcare provider or find a clinic in your area:

• Find a Genetic Clinic
• Find a Genetic Counselor