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A study led by Craig T. Basson, M.D., Ph.D., of the Molecular Cardiology Laboratory in the Division of Cardiology at Weill Cornell Medical College identifies the locus of one genetic defect responsible for familial aortic aneurysm (FAA). Ruptured aortic aneurysm is a common cause of death, and approximately one-fifth of aortic aneurysms are hereditary.

FAA is an hereditary aortic aneurysm syndrome in which aneurysms occur as an isolated cardiovascular condition—without the associated connective-tissue and skeletal abnormalities seen in Marfan or Ehlers-Danlos syndromes. FAA is an autosomal dominant trait—that is, an affected person who marries an unaffected person has a 50% chance of passing it on to each of their children.

The study, newly published in the May 22 issue of Circulation,, carries on a longstanding research focus on aortic aneurysms at New York Weill Cornell Medical Center. It was at this Medical Center that Drs. Richard Devereux and Mary Roman (who are among the co-authors of the new study) developed the innovative technique of indexed nomograms—measuring the size of the aorta by echocardiography and ultrasound and comparing it to the person's age, height, weight, and body surface area. Through these nomograms, it is possible to tell if a person is at risk of developing an aortic aneurysm.

The Molecular Cardiology investigators studied all the family members of three patients who presented at the Medical Center with aortic aneurysms. Echocardiography was performed to see if each person had aortic disease, and blood samples were taken so that DNA could be purified. None of the three families had Marfan syndrome or Ehlers-Danos syndrome.

In the first family, genetic analyses showed that the trait was not linked to any of the loci previously known to be associated with aortic aneurysm formation. These loci are fibrillin-1, fibrillin-2, and type III procollagen, and chromosome 3p24.2-p25. Rather, the analysis found a new chromosome locus, 11q23.2-q24, for the defect, which the investigators call FAA1. Statistically, this finding had a LOD score of 4.4—that is, the odds are 25,000:1 that the mutated gene causing FAA to this family is located at this chromosomal region. This is the first critical step to determining the gene(s) that cause aortic aneurysm in this and other families.

In the second family, familial aortic aneurysm was linked to fibrillin-1. Although this locus is associated with Marfan syndrome, the family did not have full Marfan syndrome, only FAA. In the third family, the analysis found that the FAA was not linked to any locus previously associated with aneurysm formation, including fibrillin-1, or to the newly discovered FAA1 gene. Thus, the investigators conclude that there are multiple gene defects that can cause FAA.

Dr. Basson, the lead author, explains, "FAA is caused by pathways of several interacting genes. In the future, new therapies developed to target the disease are likely to be aimed at a pathway involving these genes rather than at a single gene that we find today."

Future research will identify the specific gene on chromosome 11 that is mutated in FAA and will determine additional genetic loci for FAA disease. Further characterization of the FAA1 gene will enhance the ability to diagnose aortic aneurysms before symptoms develop and will define the molecular mechanisms necessary to treat the disease with novel therapies.

Joining Dr. Basson as collaborating authors of the study are Carl J. Vaughan, M.D.; Mairead Casey, B.A.; Jie He, M.D.; Mark Veugelers, Ph.D.; Kierstein Henderson, B.Sc.; Dongchuan Guo, Ph.D.; Robert Campagna, M.D.; Mary J. Roman, M.D.; Dianna M. Milewicz, M.D., Ph.D.; and Richard B. Devereux, M.D. All are from Weill Cornell, except Drs. Guo and Milewicz, who are from the University of Texas-Houston Medical School.

The study was supported by funds from the National Marfan Foundation, the New York Academy of Medicine, the Michael Wolk Cardiovascular Foundation, Cornell Vascular Medicine Research Foundation, and the Tom and Salsey Sullivan Foundation.