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Variants of Unknown Significance in Genes Associated with Heritable Thoracic Aortic Disease Can Be Low Penetrant “Risk Variants”

Published on Jul 1, 2018in American Journal of Human Genetics9.924
· DOI :10.1016/j.ajhg.2018.05.012
Callie S. Kwartler13
Estimated H-index: 13
(University of Texas Health Science Center at Houston),
Li-MinGONG23
Estimated H-index: 23
(University of Texas Health Science Center at Houston)
+ 9 AuthorsDianna M. Milewicz58
Estimated H-index: 58
(University of Texas Health Science Center at Houston)
Abstract
Thoracic aortic aneurysms leading to acute aortic dissections are a preventable cause of premature deaths if individuals at risk can be identified. Individuals with early-onset aortic dissections without a family history or syndromic features have an increased burden of rare genetic variants of unknown significance (VUSs) in genes with pathogenic variants for heritable thoracic aortic disease (HTAD). We assessed the role of VUSs in the development of disease using both in vitro enzymatic assays and mouse models. VUSs in LOX and MYLK identified in individuals with acute aortic dissections were assayed to determine whether they disrupted enzymatic activity. A subset of VUSs reduced enzymatic activity compared to the wild-type proteins but less than pathogenic variants. Additionally, a Myh11 variant, p.Arg247Cys, which does not cause aortic disease in either humans or mice, was crossed with the Acta2−/− mouse, which has aortic enlargement with age while Acta2+/− mice do not. Acta2+/−Myh11R247C/R247C mice have aortic dilation by 3 months of age without medial degeneration, indicating that two variants not known to cause disease do lead to aortic enlargement in combination. Furthermore, the addition of Myh11R247C/R247C to the Acta2−/− mouse model accelerates aortic enlargement and increases medial degeneration. Therefore, our results emphasize the need for a classification system for variants in Mendelian genes that goes beyond the 5-tier system of pathogenic, likely pathogenic, VUS, likely benign, and benign, and includes a designation for low-penetrant "risk variants" that trigger disease either in combination with other risk factors or in a stochastic manner.
  • References (17)
  • Citations (5)
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References17
Newest
#1Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 33
#2Ellen S. Regalado (University of Texas Health Science Center at Houston)H-Index: 25
Last. Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
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The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs ∗ 25 and p.Glu750 ∗...
11 CitationsSource
An acute aortic dissection is a life-threatening cardiovascular condition that is preventable if individuals at risk are identified. Pathogenic variants in 11 genes confer a highly penetrant, dominantly inherited risk for aortic aneurysms and dissections with or without syndromic features (e.g.,
7 CitationsSource
#1Jiyuan Chen (University of Texas Health Science Center at Houston)H-Index: 5
#2Andrew M. Peters (University of Texas Health Science Center at Houston)H-Index: 4
Last. Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
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Rationale: Mutations in ACTA2 , encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. Objective: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. Methods and Results: Acta2 −/− mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losart...
16 CitationsSource
#1Dianna M. MilewiczH-Index: 58
Last. Francesco Ramirez (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 68
view all 3 authors...
Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical tran...
29 CitationsSource
#1Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
#2Kathleen M. TrybusH-Index: 46
Last. James T. StullH-Index: 66
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The importance of maintaining contractile function in aortic smooth muscle cells (SMCs) is evident by the fact that heterozygous mutations in the major structural proteins or kinases controlling co...
36 CitationsSource
#1Hao Wei (UW: University of Washington)H-Index: 13
#2Jie Hong Hu (UW: University of Washington)H-Index: 8
Last. David A. Dichek (UW: University of Washington)H-Index: 35
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BackgroundMarfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin‐1 (FBN1); however, the mechanisms through which fibrillin‐1 deficiency causes MFS‐associated aortopathy are unc...
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#1Matias Hannuksela (Umeå University)H-Index: 3
#2Eva-Lena Stattin (Umeå University)H-Index: 17
Last. Bo Carlberg (Umeå University)H-Index: 29
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Background: Mutations in MYLK cause non- syndromic familial thoracic aortic aneurysms and dissections (FTAAD). Very little is known about the phenotype of affected families. We sought to characteri ...
10 CitationsSource
#1Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 33
#2Ellen S. Regalado (University of Texas Health Science Center at Houston)H-Index: 25
Last. Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
view all 20 authors...
54 CitationsSource
#1Ashkan Karimi (University of Texas Health Science Center at Houston)H-Index: 7
#2Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
The medial layer of the aorta confers elasticity and strength to the aortic wall and is composed of alternating layers of smooth muscle cells (SMCs) and elastic fibres. The SMC elastin-contractile unit is a structural unit that links the elastin fibres to the SMCs and is characterized by the following: (1) layers of elastin fibres that are surrounded by microfibrils; (2) microfibrils that bind to the integrin receptors in focal adhesions on the cell surface of the SMCs; and (3) SMC contractile f...
34 CitationsSource
#1Lior Zilberberg (NYU: New York University)H-Index: 13
#2Colin K.L. Phoon (NYU: New York University)H-Index: 25
Last. Daniel B. Rifkin (NYU: New York University)H-Index: 100
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Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has be...
18 CitationsSource
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#1MP MassettH-Index: 1
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Mutations in ACTA2, encoding smooth muscle α-actin, are a frequent cause of heritable thoracic aortic aneurysm and dissections. These mutations are associated with impaired vascular smooth muscle c...
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#1Nicolai P. OstbergH-Index: 1
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Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural history of TAAD has shown a clear genetic basis for the disease. Here, we review both the cellular mechanisms and clinical manifestations of syndromic and non-syndromic TAAD. We particularly focus on g...
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#2Carmen M. HalabiH-Index: 8
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#1De Backer J (Ghent University Hospital)H-Index: 41
#2Antoine Bondue (ULB: Université libre de Bruxelles)H-Index: 12
Last. Jolien W. Roos Hesselink (EUR: Erasmus University Rotterdam)H-Index: 1
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Thanks to a better knowledge of the genetic causes of many diseases and an improvement in genetic testing techniques, genetics has gained an important role in the multidisciplinary approach to diag...
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#1Brooke N. Wolford (UM: University of Michigan)H-Index: 8
#2Whitney Hornsby (UM: University of Michigan)H-Index: 6
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Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients o...
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#1Amélie Pinard (University of Texas Health Science Center at Houston)H-Index: 2
#2Gregory T. Jones (University of Otago)H-Index: 32
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#1Brooke N. Wolford (UM: University of Michigan)H-Index: 8
#2Whitney Hornsby (UM: University of Michigan)H-Index: 6
Last. Bo Yang (UM: University of Michigan)H-Index: 12
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Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pa...
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