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


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.
Khau Van Kien
Philippe
P
INSERM U36 and Collège de France, Paris, France.
Mathieu
Flavie
F
Zhu
Limin
L
Lalande
Alain
A
Betard
Christine
C
Lathrop
Mark
M
Brunotte
François
F
Wolf
Jean-Eric
JE
Jeunemaitre
Xavier
X
D001011:Aorta / Q000503:physiopathology; D017545:Aortic Aneurysm, Thoracic / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D001019:Aortic Rupture / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D004374:Ductus Arteriosus, Patent / Q000150:complications / Q000235:genetics*; D005192:Family Health; D008040:Genetic Linkage; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D019028:Magnetic Resonance Imaging, Cine; D010375:Pedigree; D014655:Vascular Resistance