Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder

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. Ot her 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 th e diagnostic criteria for either Marfan or Ehlers-Danlos syndrome. Echocard iography defined involvement of both the thoracic and abdominal aorta. In f amily ANA, candidate gene analysis excluded linkage to loci associated with aneurysm formation, including fibrillin-1, fibrillin-2, and type III proco llagen, 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 multipoi nt logarithm of the odds score of 4.4. In family ANB, FAA was linked to fib rillin-1. In family ANF, however, FAA was not linked to any locus previousl y 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 elucidati ng 1 gene defect responsible for aortic dilatation. Future characterization of the FAA1 gene will enhance our ability to achieve presymptomatic diagno sis of aortic aneurysms and will define molecular mechanisms to target ther apeutics.