Match!

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 Genetics9.92
· DOI :10.1016/j.ajhg.2018.05.012
Callie S. Kwartler11
Estimated H-index: 11
(University of Texas Health Science Center at Houston),
Li-MinGONG22
Estimated H-index: 22
(University of Texas Health Science Center at Houston)
+ 9 AuthorsDianna M. Milewicz56
Estimated H-index: 56
(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 +/− Myh11 R247C/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 Myh11 R247C/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 (2)
References17
Newest
#1Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 32
#2Ellen S. Regalado (University of Texas Health Science Center at Houston)H-Index: 24
Last.Stephanie Wallace (University of Texas Health Science Center at Houston)H-Index: 3
view all 17 authors...
#1Jiyuan Chen (University of Texas Health Science Center at Houston)H-Index: 4
#2Andrew M. Peters (University of Texas Health Science Center at Houston)H-Index: 4
Last.K. L. Byanova (University of Texas Health Science Center at Houston)H-Index: 4
view all 20 authors...
#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: 34
view all 8 authors...
#1Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 32
#2Ellen S. Regalado (University of Texas Health Science Center at Houston)H-Index: 24
Last.Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 56
view all 20 authors...
Cited By2
Newest
#1Brooke N. Wolford (UM: University of Michigan)H-Index: 4
#2Whitney Hornsby (UM: University of Michigan)H-Index: 6
Last.Ellen M. SchmidtH-Index: 17
view all 24 authors...
#1Amélie Pinard (University of Texas Health Science Center at Houston)H-Index: 2
#2Gregory T. Jones (University of Otago)H-Index: 30
Last.Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 56
view all 3 authors...
#1Brooke N. Wolford (UM: University of Michigan)H-Index: 4
#2Whitney Hornsby (UM: University of Michigan)H-Index: 6
Last.Ellen M. SchmidtH-Index: 17
view all 24 authors...
View next paperLOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections