Mapping of familial thoracic aortic aneurysm/dissection with patent ductus arteriosus to 16p12.2-p13.13

Circulation. 2005 Jul 12;112(2):200-6. doi: 10.1161/CIRCULATIONAHA.104.506345. Epub 2005 Jul 5.


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 theta=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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aorta / physiopathology
  • Aortic Aneurysm, Thoracic / diagnosis
  • Aortic Aneurysm, Thoracic / etiology
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Rupture / diagnosis
  • Aortic Rupture / etiology
  • Aortic Rupture / genetics*
  • Chromosome Mapping*
  • Chromosomes, Human, Pair 16*
  • Ductus Arteriosus, Patent / complications
  • Ductus Arteriosus, Patent / genetics*
  • Family Health
  • Genetic Linkage
  • Genome, Human
  • Haplotypes
  • Humans
  • Lod Score
  • Magnetic Resonance Imaging, Cine
  • Pedigree
  • Vascular Resistance