When a disease touches millions of lives, the silver lining is that it can be easier to find funding for research to prevent or cure it.
However, if someone is suffering from one of the thousands of diseases caused by a rare genetic variant, it has usually been difficult to find answers that would result in treatment, leaving the idea of a cure to be a distant hope.
That, to some degree, may at last be changing.
"In the past, the first challenge was to determine whether an unknown condition pattern had a genetic basis," Bruce Korf, MD, PhD, Director of the UAB Department of Genetics, said. "There are sometime constellations of clinical problems that form a pattern similar to something that has been seen before. Other members of a family may have the same or similar symptoms. The effects may be complex or involve a pairing of multiple body systems such as the heart and kidneys, intellectual disabilities, or distinct physical features.
"With more than 7,000 known genetic disorders, many are difficult to recognize without testing, even if a test exists. In fact, tests for hundreds of genetic disorders are available, but unless there is a way to narrow the list, attempting even a small percentage of them would involve an overwhelming amount of time and expense."
The advent of more affordable genomic sequencing now makes it practical to test 22,000 genes simultaneously.
"About a third of the time, we have a clear answer when the results come back," Korf said. "Sometimes it is something we simply hadn't thought of before. Another third leaves us with questions that science isn't able to answer yet, but may be able to answer in the future. The final third puts us in a middle ground where we identify variants that aren't commonly seen and may be difficult to prove as being the source of the problem, but there are indications you are on the right track.
"This is where international databases can be helpful. The NIH has a catalog of conditions associated with specific variants. If you don't find an answer there, you can go to the Matchmaker Exchange online. There you can describe the variant you have found on that specific gene and post details about symptoms you are observing. You may find that someone in Germany has a patient with the same variant and similar symptoms, and when you exchange emails, you find that the patients look enough alike to be brothers."
When the mystery of which of millions of possible variants are significant remains unsolved, how do you narrow the possibilities?
"Using informatics, we can filter out more common genetic disorders that would probably be recognized," Korf said. "You can also filter for variants that tend to have more severe effects, and may also be able to search for those that are likely to be expressed in specific body systems.
"Another possibility is to sequence other family members to determine if they have a variant in common that isn't usually seen in most people. If a baby has a variant neither parent has, it is likely a new mutation. If a child has two copies of a gene and each parent has only one, a recessive gene is likely to be involved.
"An excess or deficiency of certain proteins in the bloodstream can also be a clue that other genes are influencing how a variant is expressed."
What are the benefits for patients when the genetic basis of a rare disease is found?
"For some, it's the peace of mind of finally knowing what is going on," Korf said. "If we can find someone else half a world away who has experienced the same disease, we can look at how their symptoms progressed to help us manage the disease. We may find that the other patient developed kidney disease, so we will have an early warning to help reduce risks."
As researchers learn more about the nature of rare genetic disorders, they are often finding that existing medications may be effective in treating symptoms.
"The more we learn about rare diseases, the more help we can offer patients," Korf said. "Neurofibromatosis is one of those relatively rare diseases that has been a focus of my research. Until recently, there was little we could offer these patients. Now we're in clinical trials testing medications that at last show hope of providing the kind of help these patients have been seeking for so long."