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(Circulation. 2005;112:200-206.)
© 2005 American Heart Association, Inc.

Genetics

Mapping of Familial Thoracic Aortic Aneurysm/Dissection With Patent Ductus Arteriosus to 16p12.2–p13.13

Philippe Khau Van Kien, MD^*; Flavie Mathieu, PhD^*; Limin Zhu, MD; Alain Lalande, PhD; Christine Betard, PhD; Mark Lathrop, MD, PhD; François Brunotte, MD, PhD; Jean-Eric Wolf, MD, PhD; Xavier Jeunemaitre, MD, PhD

From INSERM U36 and Collège de France; Département de Génétique, Hôpital Européen Georges Pompidou, Assistance Publique, Hôpitaux de Paris; and Faculté de Médecine Paris-Descartes, Paris (P.K.V.K., F.M., L.Z., K.J.); Laboratoire de Pharmacologie et de Physiopathologie Cardiovasculaire Expérimentale, CHU Dijon, and Université de Bourgogne, Dijon (P.K.V.K., F.B., J.-E.W.); Service de Cardiologie II (P.K.V.K., J.-E.W.) and Centre d’IRM (A.L., F.B.), CHU Dijon, Dijon; and Centre National de Génotypage, Evry (C.B., M.L.), France.

Correspondence to Xavier Jeunemaitre, MD, PhD, Collège de France, INSERM U36, 11, Place Marcelin Berthelot, 75005 Paris, France. E-mail xavier.jeunemaitre{at}college-de-france.fr or xavier.jeunemaitre@egp.aphp.fr

Received September 12, 2004; revision received March 8, 2005; accepted March 30, 2005.

Background— Three loci have been shown to be responsible for nonsyndromic familial thoracic aortic aneurysms (TAAs) and aortic dissections (ADs). We recently described a large family in which TAA/AD associates with patent ductus arteriosus (PDA) and provided genetic arguments for a unique pathophysiological entity.

Methods and Results— Genome-wide scan was performed in 40 subjects belonging to 3 generations in this large pedigree. Using the 7 TAA/AD cases as affected, we observed positive 2-point LOD scores on adjacent markers at chromosome 16p, with a maximum LOD score value of 2.73 at =0, a value that increased to 3.56 when 5 PDA cases were included. Multipoint linkage analysis yielded a maximum LOD score of 4.14 in the vicinity of marker D16S3103. Fine mapping allowed the observation of recombinant haplotypes that delimited a critical 20-cM interval at 16p12.2-p13.13. Automatic determination of aortic compliance with cine MRI showed that all subjects bearing the disease haplotype, even asymptomatic, displayed a very low level of aortic compliance and distensibility. Aortic stiffness was strongly associated with disease haplotype with a marked effect of age, indicating subclinical and early manifestation of the disease.

Conclusions— Genetic analysis of this family identified a unique locus responsible for both TAA/AD and PDA at chromosome 16p12.2-p13.13 with aortic stiffness as an early hallmark of the disease. TAA/AD with PDA is a new monogenic entity among the genetically heterogeneous group of TAA/AD disease.

Key Words: aneurysm • aorta • ductus arteriosus • genetics • mapping

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