(Circulation. 2001;103:2469.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Identification of a Chromosome 11q23.2-q24 Locus for Familial Aortic Aneurysm Disease, a Genetically Heterogeneous Disorder
From the Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, The New York Presbyterian Hospital (C.J.V., M.C., J.H., M.V., R.C., M.J.R., R.B.D., C.T.B.), and the Cell Biology and Genetics Program, Weill Graduate School of Medical Sciences of Cornell University (K.H., C.T.B.), New York, NY; and the Department of Internal Medicine, University of Texas–Houston Medical School, Houston, Tex (D.G., D.M.M.).
Correspondence to Craig T. Basson, MD, PhD, Director, Molecular Cardiology Laboratory, Cardiology Division, Department of Medicine, Weill Medical College of Cornell University, 525 E 68th St, New York, NY 10021. E-mail ctbasson{at}med.cornell.edu
Background—Aortic aneurysms cause significant mortality, and >20% relate to hereditary disorders. Familial aortic aneurysm (FAA) has been described in such conditions as the Marfan and Ehlers-Danlos type IV syndromes, due to defects in the fibrillin-1 and type III procollagen genes, respectively. Other gene defects that cause isolated aneurysms, however, have not thus far been described.
Methods and Results—We studied 3 families affected by FAA. No family met the diagnostic criteria for either Marfan or Ehlers-Danlos syndrome. Echocardiography defined involvement of both the thoracic and abdominal aorta. In family ANA, candidate gene analysis excluded linkage to loci associated with aneurysm formation, including fibrillin-1, fibrillin-2, and type III procollagen, and chromosome 3p24.2-p25. Genome-wide linkage analysis identified a 2.3-cM FAA locus (FAA1) on chromosome 11q23.3-q24 with a maximum multipoint logarithm of the odds score of 4.4. In family ANB, FAA was linked to fibrillin-1. In family ANF, however, FAA was not linked to any locus previously associated with aneurysm formation, including fibrillin-1 and FAA1.
Conclusions—FAA disease is genetically heterogeneous. We have identified a novel FAA locus at chromosome 11q23.3-q24, a critical step toward elucidating 1 gene defect responsible for aortic dilatation. Future characterization of the FAA1 gene will enhance our ability to achieve presymptomatic diagnosis of aortic aneurysms and will define molecular mechanisms to target therapeutics.
Key Words: aneurysm • aorta • genetics • mapping
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