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

Callie S. Kwartler, Limin Gong, Jiyuan Chen, Shanzhi Wang, Richard Kulmacz, Xue yan Duan, Alexandra Janda, Jian Huang, Kristine E. Kamm, James T. Stull, Dongchuan Guo, Dianna M. Milewicz

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)138-143
Number of pages6
JournalAmerican Journal of Human Genetics
Issue number1
StatePublished - Jul 5 2018


  • aortic dissection
  • heritable thoracic aortic diseases
  • variant classification
  • variants of unknown significance

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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