(Circulation. 2001;103:2461.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Familial Thoracic Aortic Aneurysms and Dissections
Genetic Heterogeneity With a Major Locus Mapping to 5q13-14
From the Department of Internal Medicine, University of Texas–Houston Medical School (D.G., S.H., S.-Q.K., H.C., D.M.M.); Department of Medicine, Cornell University Medical College, New York Hospital, New York, NY (C.J.V., C.T.B.); Human Genetic Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.); Department of Pediatrics, Rhode Island Hospital and Brown University School of Medicine, Providence, RI (D.A.); Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Md (H.C.D.); and Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston (S.S.S.).
Correspondence to Dianna M. Milewicz, MD, PhD, Department of Internal Medicine, University of Texas–Houston Medical School, 6431 Fannin, MSB 1.614, Houston, TX 77030. E-mail dianna.m.milewicz{at}uth.tmc.edu
Background—Aneurysms and dissections affecting the ascending aorta are associated primarily with degeneration of the aortic media, called medial necrosis. Families identified with dominant inheritance of thoracic aortic aneurysms and dissections (TAA/dissections) indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome.
Methods and Results—Fifteen families were identified with multiple members with TAAs/dissections. DNA from affected members from 2 of the families was used for a genome-wide search for the location of the defective gene by use of random polymorphic markers. The data were analyzed by the affected-pedigree-member method of linkage analysis. This analysis revealed 3 chromosomal loci with multiple markers demonstrating evidence of linkage to the phenotype. Linkage analysis using further markers in these regions and DNA from 15 families confirmed linkage of some of the families to 5q13-14. Genetic heterogeneity for the condition was confirmed by a heterogeneity test. Data from 9 families with the highest conditional probability of being linked to 5q were used to calculate the pairwise and multipoint logarithm of the odds (LOD) scores, with a maximum LOD of 4.74, with no recombination being obtained for the marker D5S2029. In 6 families, the phenotype was not linked to the 5q locus.
Conclusions—A major locus for familial TAAs and dissections maps to 5q13-14, with the majority (9 of 15) of the families identified demonstrating evidence of linkage to this locus. The condition is genetically heterogeneous, with 6 families not demonstrating evidence of linkage to any loci previously associated with aneurysm formation.
Key Words: aorta • aneurysm • genetics
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