April - June 2011: GJC2 Mutations Cause Primary Lymphedema

By: Michael Bernas MS

Q: My daughter has been diagnosed with primary lymphedema. What are the chances this is due to a genetic alteration?

A: This is probably the most common question asked by patients who have been diagnosed with primary lymphedema. Unfortunately, the answer is not always easy or possible to find. We are still early in the field of genetics concerning lymphedema, and much more research and findings are needed. The simple answer is that when looking at the total population of patients with primary lymphedema, only a small percentage (maybe 10%, but unknown) of the patients have causative genetic alterations. The more deeply you investigate, the more complex things become. Some genetic changes (termed mutations) may be sporadic, meaning they just appeared in this child, and others may have existed for some time in the family history. Every patient with a suspected genetic condition should have a good history, and particularly, a thorough physical examination by a knowledgeable physician to define the lymphatic phenotype (how the person exhibits their lymphedema and associated symptoms and signs). This examination should also include a detailed family history which can show if the condition has been inherited and how it was inherited (whether the alteration is caused by a dominant gene from a single parent or a recessive gene from each parent). Using these two pieces of information, the clinician can gain a better understanding of the patient and determine if the condition is caused by a genetic alteration. Presently we know of several genes involved with lymphedema, and the patient’s phenotype may resemble one of these conditions. Further testing can be done to genotype the individual (to look at the genes or genetic code). Currently, this sophisticated testing occurs only at a few specialized medical centers and clinical laboratory testing sites. Therefore, laboratory testing is limited for most patients. If a mutation in one of the known genes is confirmed, then the patient does have a genetic alteration. However, if a change in one of the known genes is not present, this does not necessarily mean the condition is not related to a genetic change, but only that our knowledge may be too limited at the present time to make the determination.

Q: I have been told that the lymphedema in our family appears to be an inherited condition; what are the chances of having another child with lymphedema and what are the chances of my child having a son or daughter with lymphedema?

A: This is an important follow-up question that is also frequently asked. The answer relies on the type of genetic change that has been identified by the family and through genetic studies. If the change has been found to be a dominant condition, then the chances of a second child with lymphedema are 50%. If the change is a recessive condition, the chances reduce to 25% with the same father. For the following generation (grandchildren), a mother carrying the dominant mutation would have a 50% chance of passing the condition on to her children. Concurrently, a mother with a recessive mutation would have a 0-25% chance depending on the genotype of the father. We have to realize that these are the odds over large populations, and the chances for an individual family have to be weighed against these odds. In addition, just having the genetic change does not mean that the individual will show the lymphedema, and individuals could also have a milder or no apparent abnormality (known as carrier of the genetic trait). These statistics will also vary since there are still more genes to be discovered, some conditions may have more than one gene involved, and there may be other modes of inheritance (i.e. sex-linked).

Q: What does the future of lymphedema genetics look like? 

A: Although discoveries are always right around the corner, there is still much work to be done. There are on-going studies of families to find more genes related to lymphedema and the lymphatic system. Although there are approximately 40 inherited syndromes with associated lymphedema, so far we only know of a few genes that cause these conditions. Additionally, there are many studies conducted at research laboratories that focus on finding more genes and proteins that are linked to the lymphatic system. Despite these discoveries, linking them to genetic disorders in patients has been difficult. Hopefully, the future will continue to bring us more discoveries, more sensitive detection methods and markers, and also the ability to treat these genetic conditions.

michaelb [at] u.arizona.edu