Identification of a Chromosome 11q23.2-q24 Locus for Familial Aortic Aneurysm Disease, a Genetically Heterogeneous Disorder

Vaughan, Carl J.; Casey, Mairead; He, Jié; Veugelers, Mark; Henderson, Kiersten A.; Guo, Dongchuan; Campagna, R.J.; Roman, Mary J.; Milewicz, Dianna M.; Devereux, Richard B.; Basson, Craig T.

doi:10.1161/01.cir.103.20.2469

Cited by 165 publications

(95 citation statements)

References 30 publications

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“…Linkage to these loci, as well as linkage to the loci on chromosomes 3, 11 5 9 and 11 was ruled out. 10 Moreover, DNA sequencing of COL3A1 cDNA in three affected subjects detected no mutation within the entire coding sequence (data not shown). The exclusion of linkage was even stronger when subjects with PDA were considered to be affected rather than as unknown.…”

Section: Discussionmentioning

confidence: 89%

“…4 To date, two genes have been identified: COL3A1 (type III procollagen ) 5,6 and FBN1 (fibrillin-1) 7,8 Two loci for nonsyndromic familial TAA/AD have been mapped to 5q13 -q14 and 11q23.2 -24 and called TAAD1 9 and FAA1, respectively. 10 More recently, another locus for nonsyndromic familial TAA/AD was mapped to 3p24 -25 and termed TAAD2. 11 It overlaps a previously mapped second locus for MFS (MFS2).…”

Section: Introductionmentioning

confidence: 99%

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Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity

et al. 2004

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Thoracic aortic aneurysm and aortic dissection (TAA and AD) are an important cause of sudden death. Familial cases could account for 20% of all cases. A genetic heterogeneity with two identified genes (FBN1 and COL3A1) and three loci (3p24-25 or MFS2/TAAD2, 5q13 -q14 and 11q23.2-24) has been shown previously. Study of a single family composed of 179 members with an abnormally high occurrence of TAA/ AD disease. A total of 40 subjects from three generations were investigated. In addition to five cases of stroke and three cases of sudden death, there were four cases of AD and four cases of TAA in adults. In all, 11 cases of patent ductus arteriosus (PDA) were observed, two of which were associated with TAA and one with AD. Segregation analysis showed that the distribution of these vascular abnormalities was more likely compatible with a single genetic defect with an autosomal dominant pattern of inheritance. There were no clinical signs of Marfan, Elhers -Danlos vascular type or Char syndromes. Genetic linkage analysis was performed for seven genes or loci implicated in familial TAA/AD disease (COL3A1, FBN1, 3p24-25 or MFS2/ TAAD2, 5q13-q14 and 11q23.2 -q24), Char syndrome (TFAP2B) or autosomal recessive PDA (12q24). Using different genetic models, linkage with these seven loci was excluded. Familial TAA/AD with PDA is likely to be a particular heritable vascular disorder, with an as yet undiscovered Mendelian genetic basis.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity

et al. 2004

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“…Our results also suggest that genetic testing and cardiac imaging with at least TTE should be offered to all FDRs and SDRs of patients with suspected NS‐TADs. Mutation carriers should undergo further imaging (MRI or CT scan), focusing on thoracic aorta and/or other arterial trees based on the causative gene mutation 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74. For example, ACTA2‐mutation carriers should be monitored for coronary artery disease and occlusive cerebrovascular disease, in addition to the currently recommended routine imaging tests 32.…”

Section: Discussionmentioning

confidence: 99%

“…First, variable penetrance, which often characterizes NS‐TAD forms, is a potential confounder. This results in intrafamilial variability, which is evident not only with reference to the aortopathy itself (severity, age of onset), but also with regard to other phenotypic manifestations 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81. The presence of associated features is certainly suggestive of having inherited the aortic condition along with the predisposition to the aortopathy, but the absence of these associated features does not eliminate the risk of having an underlying aortopathy.…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

Mariscalco

Debiec

Elefteriades

et al. 2018

JAHA

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BackgroundNonsyndromic thoracic aortic diseases (NS‐TADs) are often silent entities until they present as life‐threatening emergencies. Despite familial inheritance being common, screening is not the current standard of care in NS‐TADs. We sought to determine the incidence of aortic diseases, the predictive accuracy of available screening tests, and the effectiveness of screening programs in relatives of patients affected by NS‐TADs.Methods and ResultsA systematic literature search on PubMed/MEDLINE, Embase, and the Cochrane Library was conducted from inception to the end of December 2017. The search was supplemented with the Online Mendelian Inheritance in Man database. A total of 53 studies were included, and a total of 2696 NS‐TAD relatives were screened. Screening was genetic in 49% of studies, followed by imaging techniques in 11% and a combination of the 2 in 40%. Newly affected individuals were identified in 33%, 24%, and 15% of first‐, second‐, and third‐degree relatives, respectively. Familial NS‐TADs were primarily attributed to single‐gene mutations, expressed in an autosomal dominant pattern with incomplete penetrance. Specific gene mutations were observed in 25% of the screened families. Disease subtype and genetic mutations stratified patients with respect to age of presentation, aneurysmal location, and aortic diameter before dissection. Relatives of patients with sporadic NS‐TADs were also found to be affected. No studies evaluated the predictive accuracy of imaging or genetic screening tests, or the clinical or cost‐effectiveness of an NS‐TAD screening program.ConclusionsFirst‐ and second‐degree relatives of patients affected by both familial and sporadic NS‐TADs may benefit from personalized screening programs.

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“…[15][16][17] Despite the subtle genetic differences between connective-tissue disorders and familial TAA/dissection syndrome, the common denominator among many of these genetic conditions is breakdown of the elastic fiber milieu, involving chromosomal loci 5q13-14 and 11q23.2-q24. 18,19 Annuloaortic ectasia refers to the process in which elastolysis occurs in the aortic annulus. Such histologic changes cause weakening of the aortic wall and thus aneurysm and dissection of the ascending aorta.…”

Section: Aortic Dissectionmentioning

confidence: 99%

Acute Aortic Syndromes and Thoracic Aortic Aneurysm

Ramanath

Sundt

et al. 2009

Mayo Clinic Proceedings

195

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Acute and chronic aortic diseases have been diagnosed and studied by physicians for centuries. Both the diagnosis and treatment of aortic diseases have been steadily improving over time, largely because of increased physician awareness and improvements in diagnostic modalities. This comprehensive review discusses the pathophysiology and risk factors, classification schemes, epidemiology, clinical presentations, diagnostic modalities, management options, and outcomes of various aortic conditions, including acute aortic dissection (and its variants intramural hematoma and penetrating aortic ulcers) and thoracic aortic aneurysms. Literature searches of the PubMed database were conducted using the following keywords: aortic dissection, intramural hematoma, aortic ulcer, and thoracic aortic aneurysm. Retrospective and prospective studies performed within the past 20 years were included in the review; however, most data are from the past 15 years. and studied by physicians for centuries. Descriptions of such pathologic conditions of the aorta as aneurysm and dissection date back as early as the 2nd century during the time of Galen, whose discoveries were largely made through studies of apes. More "recent" reports were described by Vesalius in 1557, followed by Nichols in 1732, who detailed the process of aortic dissection. In 1761, Morgagni reported detailed pathologic features of a patient with a ruptured aorta. 1 However, our true understanding of aortic pathology began with the dissertation by Shennan 2 in 1934, which included a description of penetrating atheromatous plaques of the thoracic aorta. His report was followed by the first successful management of aortic dissection by DeBakey in 1955. 1 Since then, our knowledge of the pathologic conditions of the aorta has grown considerably and continues to evolve with ongoing research into the pathophysiology of these conditions, technological advances in the modes of detection, and improved therapeutic options. Clinical databases, such as the International Registry of Acute Aortic Dissection (IRAD), the largest current registry for acute aortic syndromes, have also contributed tremendously to our knowledge of acute aortic pathology.For the practicing clinician, knowledge of aortic disease is paramount because patients with aortic conditions contribute significantly to the overall mortality from cardiovascular disease. This review discusses the pathophysiology, epidemiology, presentation, diagnosis, and therapeutic options for several forms of acute and chronic aortic pathology: aortic dissection (including its variants intramural hematoma [IMH] and penetrating atheromatous aortic ulcer) and thoracic aortic aneurysm (TAA). Literature searches were performed of the PubMed database using the following key words: aortic dissection, intramural hematoma, aortic ulcer, and thoracic aortic aneurysm. Retrospective and prospective studies conducted within the past 15 years, along with some data from years prior, were included in this review.

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Identification of a Chromosome 11q23.2-q24 Locus for Familial Aortic Aneurysm Disease, a Genetically Heterogeneous Disorder

Cited by 165 publications

References 30 publications

Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity

Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

Acute Aortic Syndromes and Thoracic Aortic Aneurysm

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