The Lymphedema Family Study aims to determine precisely how lymphedema is inherited in families. Our hope is that identification of the genes responsible for primary lymphedema will provide a better understanding of its cause, and aid in the development of new and better methods for diagnosing and treating lymphedema. The Lymphedema Family Study is a linkage study. Linkage studies, also called linkage analysis, involve a comparison of genetic material between family members with and without lymphedema. In large families this allows the identification of markers on a chromosome, that are associated with a gene responsible for lymphedema. These markers indicate the chromosomal location of that gene. Further research then allows the identification of the causative gene. So far, three genes have been identified that cause primary lymphedema: VEGFR3, FOXC2, and in very rare cases SOX18. More recently, our research suggests that two additional genes, HGF and MET, are also responsible for the development of lymphedema in some families.
Vascular endothelial growth factor receptor 3 (VEGFR3) was the first lymphedema gene to be identified. VEGFR3, which was formerly known as FLT4, is located on chromosome 8 and is known to be involved in the formation of lymphatic vessels during prenatal development. VEGFR3 causes congenital lymphedema (swelling which is present from birth). To date we have identified lymphedema-causing genetic changes (mutations) in 12 participating families.
Our article entitled "Hereditary Lymphedema: Evidence for Linkage and Genetic Heterogeneity" which was published in the December, 1998 issue of the scientific journal Human Molecular Genetics, was the first publication to identify VEGFR3 as causative for congenital familial lymphedema, also know as Milroy’s Disease. Another article written by our research group, entitled "Missense mutations interfere with VEGFR3 signalling in primary lymphoedema," describes the affect of 4 different mutations in the VEGFR3 gene. It was published in June, 2000 in the scientific journal Nature Genetics.
FOXC2 was the second lymphedema gene to be identified. It is responsible for causing the lymphedema-distichiasis syndrome (LD). Individuals with LD have lymphedema of pubertal or adult onset as well as distichiasis, which is the presence of extra eyelashes. These eyelashes may simply appear long and thick, or they may become ingrown and irritate the eye, in which case they are often removed. Less frequently, individuals with LD may be born with a heart defect, cleft palate (opening in the roof of the mouth), or ptosis (droopy eyelids). We have identified changes or mutations in the FOXC2 gene in 17 families participating in the Lymphedema Family Study.
Lymphedema-distichiasis was first localized to chromosome 16 in 1999 by Mangion et al. in an article entitled "A gene for lymphedema-distichiasis maps to 16q24.3." However, FOXC2 was not identified as the causative gene until 2001 by Fang at al in an article entitled "Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome." Our paper on FOXC2, entitled "Truncating mutations in FOXC2 cause multiple lymphedema syndromes," was published in Human Molecular Genetics also in the year 2001.
Hepatocyte growth factor (HGF) and its receptor MET are both located on chromosome 7. The HGF/MET biologic pathway is thought to play a role in the growth and development of lymphatic vessels. To date we have identified 4 primary lymphedema patients with mutations in the HGF gene and 4 others with MET mutations. Our article entitled "HGF and MET mutations in primary and secondary lymphedema," was published in 2008 in the scientific journal, Lymphatic Research and Biology.
Not all hereditary lymphedema is caused by VEGFR3, FOXC2, or HGF/MET indicating that there is at least one other gene (probably many more) responsible for hereditary lymphedema. This phenomenon, the existence of more than one gene responsible for the same condition, is called genetic heterogeneity. We are continuing to look for the locations of these additional lymphedema genes.
General results regarding the progress of the study will be made available to participants in several ways. Updates will be posted on this website, and articles will be published in the National Lymphedema Network's Newsletter whenever significant new developments have occured. In addition, if you are a participant in this study and a mutation was identified in your family, you will receive a letter with additional information about the discovery, and you will be offered the opportunity to receive your research results if you want them. Your individual research results will only be disclosed to you or, if applicable, your legal guardian, unless we are provided with written permission to release those results to another individual.
In most cases specific genetic information is not yet available for individual families or family members. However, as new genes are identified and proven to be responsible for causing lymphedema in specific families, we will continue to contact the participating family members to inform them of this finding and discuss the impact of this information on them and their families. At that time individual genetic information will be offered to those participants who are interested. However, any genetic information provided by this study will be in the form of research results only and should not be used for medical decision-making without confirmation by a laboratory offering clinical or diagnostic testing. Those individuals who receive research results may elect to have confirmatory testing from a certified diagnostic laboratory. This would involve an additional blood sample and possibly the signing of another consent form. We are currently negotiating with a local laboratory to arrange this testing at a reduced rate for study participants.
We would like to remind you that this is a research study, and therefore, we cannot guarantee that any information will be available to individual families or participants. This study does not provide diagnosis or treatment of lymphedema, and is not designed to result in any direct benefit to the participants. However, it is our hope that it will benefit lymphedema patients in the future. In addition, the participation of families and family members is voluntary and confidential. Advances in understanding the underlying cause of lymphedema are critically dependent on the participation of individuals and families in research such as ours, so for those families participating in our study, we would like to thank you once again. Should you have any questions or concerns about this information or the study in general, please don't hesitate to call Kara Levine at (412) 624-4659 or (800) 263-2152 or e-mail to firstname.lastname@example.org. Please be sure to include the word “LYMPHEDEMA” in the subject line of any e-mail.