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.
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.
Authors: Gail D Pearson; Richard Devereux; Bart Loeys; Cheryl Maslen; Dianna Milewicz; Reed Pyeritz; Francesco Ramirez; Daniel Rifkin; Lynn Sakai; Lars Svensson; Andy Wessels; Jennifer Van Eyk; Harry C Dietz Journal: Circulation Date: 2008-08-12 Impact factor: 29.690
Authors: Rumin He; Dong-Chuan Guo; Wei Sun; Christina L Papke; Senthil Duraisamy; Anthony L Estrera; Hazim J Safi; Chul Ahn; L Maximilian Buja; Frank C Arnett; Jingwu Zhang; Yong-Jian Geng; Dianna M Milewicz Journal: J Thorac Cardiovasc Surg Date: 2008-06-12 Impact factor: 5.209
Authors: Hariyadarshi Pannu; Van Tran-Fadulu; Christina L Papke; Steve Scherer; Yaozhong Liu; Caroline Presley; Dongchuan Guo; Anthony L Estrera; Hazim J Safi; Allan R Brasier; G Wesley Vick; A J Marian; C S Raman; L Maximilian Buja; Dianna M Milewicz Journal: Hum Mol Genet Date: 2007-07-31 Impact factor: 6.150
Authors: Jianhe Huang; Lan Cheng; Jian Li; Mary Chen; Deying Zhou; Min Min Lu; Aaron Proweller; Jonathan A Epstein; Michael S Parmacek Journal: J Clin Invest Date: 2008-02 Impact factor: 14.808