Because a high percentage of rare diseases have a genetic component, most undiagnosed patients benefit from evaluation at a clinical genetics center where they can receive genetic testing (for a search tool to locate clinical genetics centers in the U.S., please visit the American College of Medical Genetics and Genomics website.)
Genetic testing involves examining a person’s DNA, the structure in cells that carries the genetic code. This testing can reveal variants, or changes, in genes that can help to diagnose some rare diseases.
Genetic tests can be performed on samples of blood, skin, saliva, or other tissue. These tests can help to confirm a rare disease diagnosis and identify treatment options, including clinical trials. Most genetic tests focus on examining one gene at a time, based on a clinician’s judgement of the most likely cause for a person’s condition.
Although genetic testing often provides a diagnosis, it may be difficult to predict which of the approximately 22,000 genes in the human genome is the cause of a person’s condition.
Genome Sequencing
It is now possible to examine most or all of these genes in a single test called genome sequencing.
Genome sequencing comes in two forms: whole exome sequencing (WES) and whole genome sequencing (WGS). WES focuses just on that part of the genome that encodes for proteins. This is where most genetic variants that cause disease are located. WGS looks at the entire genome, including regions that do not encode protein.
Currently, most clinical laboratories that do genome sequencing offer WES, which is much less expensive and easier to interpret than WGS. WGS is offered on a clinical or research basis in some settings; it may be able to detect a larger number of genetic variants associated with disease, but it is also considerably more expensive to perform.
Genome sequencing identifies a genetic explanation for rare disease in 25-50% of cases. The diagnostic rate depends in part on how much information there is to support a genetic cause for a person’s rare disease in the first place. The genetic variant that is identified may be a unique one that has never been seen before.
Sometimes this results in discoveries of new genetic conditions, especially if more than one person is found with a change in the same gene. Laboratories can share information on a confidential basis to try to find similar cases that help to validate these new findings. However, sometimes genome sequencing results in finding a genetic variant that cannot be definitively concluded to be the cause of a person’s condition, though it may have features that suggest it is possibly related. Geneticists call these “variants of unknown significance,” or VUSs.
It’s important to note that a VUS is not the definitive cause of a person’s condition. Some VUSs are eventually determined to be the cause, while others are eventually found not to cause disease. Therefore, clinical decisions, such as starting treatment, should not be based on the finding of a VUS.
Even with advances in genome sequencing technology, we are still not able to detect all possible genetic changes that cause disease. Because of this, a negative result from genome sequencing does not mean that there is no genetic cause of a person’s condition. For this reason, one should not assume that genetic transmission of the condition will not occur if the sequencing was not informative.
In some cases, re-analysis of a genome sequence a year or two after the initial test reveals a variant that was not initially appreciated. This is usually because more information has been gained to help interpret variants. Genome sequencing is gradually being improved to detect specific kinds of genetic variants. If genome sequencing does not result in a diagnosis, it can be useful to maintain contact with a genetics physician to periodically explore whether there are new approaches that may shed light on the underlying diagnosis.
Alabama Genomic Health Initiative
Undiagnosed patients in Alabama may benefit from participation in the Alabama Genomic Health Initiative (AGHI). This program is one of the first statewide efforts in the nation to use the power of genomic analysis (genome sequencing) in helping to identify those who are at risk for disease and genomic abnormalities.
AGHI includes members from UAB, HudsonAlpha Institute for Biotechnology, and Tuskegee University, all of which are nationally recognized institutions and leaders in bioethics and genomic medicine.
The program includes a component of testing adults for several rare genetic conditions. These mostly include conditions that increase risk of cancer or some kinds of heart disease. The program also offers WGS for individuals with rare undiagnosed diseases.
