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.