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Am J Hum Genet. 2018 Jul 5;103(1):138-143. doi: 10.1016/j.ajhg.2018.05.012. Epub 2018 Jun 28.

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

Author information

1
Division of Medical Genetics and Cardiology, Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin Street, MSB 6.100, Houston, TX 77030, USA.
2
Division of Hematology, Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin Street, Houston, TX 77030, USA.
3
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Division of Medical Genetics and Cardiology, Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin Street, MSB 6.100, Houston, TX 77030, USA. Electronic address: dianna.m.milewicz@uth.tmc.edu.

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.

KEYWORDS:

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

PMID:
29961567
PMCID:
PMC6035370
DOI:
10.1016/j.ajhg.2018.05.012
[Indexed for MEDLINE]
Free PMC Article

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