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Case Report

Human SMAD4 Genomic Variants Identified in Individuals with Heritable and Early-Onset Thoracic Aortic Disease

1
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
2
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
3
Division of Cardiology, University of Washington School of Medicine, Seattle, WA 98195, USA
4
Genome Sciences, University of Washington, Seattle, WA 98195, USA
5
Mother Infant Research Institute, Tufts Medical Center, Boston, MA 02111, USA
*
Author to whom correspondence should be addressed.
Co-first authors.
Academic Editors: Giuseppe Limongelli and Lia Crotti
Cardiogenetics 2021, 11(3), 132-138; https://doi.org/10.3390/cardiogenetics11030015
Received: 6 May 2021 / Revised: 26 June 2021 / Accepted: 12 August 2021 / Published: 18 August 2021
(This article belongs to the Special Issue Cardiogenetics: Feature Papers 2021)
Thoracic aortic aneurysms (TAAs) that progress to acute thoracic aortic dissections (TADs) are life-threatening vascular events that have been associated with altered transforming growth factor (TGF) β signaling. In addition to TAA, multiple genetic vascular disorders, including hereditary hemorrhagic telangiectasia (HHT), involve altered TGFβ signaling and vascular malformations. Due to the importance of TGFβ, genomic variant databases have been curated for activin receptor-like kinase 1 (ALK1) and endoglin (ENG). This case report details seven variants in SMAD4 that are associated with either heritable or early-onset aortic dissections and compares them to pathogenic exon variants in gnomAD v2.1.1. The TAA and TAD variants were identified through whole exome sequencing of 346 families with unrelated heritable thoracic aortic disease (HTAD) and 355 individuals with early-onset (age ≤ 56 years old) thoracic aortic dissection (ESTAD). An allele frequency filter of less than 0.05% was applied in the Genome Aggregation Database (gnomAD exome v2.1.1) with a combined annotation-dependent depletion score (CADD) greater than 20. These seven variants also have a higher REVEL score (>0.2), indicating pathogenic potential. Further in vivo and in vitro analysis is needed to evaluate how these variants affect SMAD4 mRNA stability and protein activity in association with thoracic aortic disease. View Full-Text
Keywords: genomic variants; hereditary hemorrhagic telangiectasia; thoracic aortic aneurysm; vascular malformations; SMAD4 genomic variants; hereditary hemorrhagic telangiectasia; thoracic aortic aneurysm; vascular malformations; SMAD4
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MDPI and ACS Style

Bhave, S.A.; Guo, D.; Angelov, S.N.; Bamshad, M.J.; Nickerson, D.A.; Milewicz, D.M.; Wallingford, M.C. Human SMAD4 Genomic Variants Identified in Individuals with Heritable and Early-Onset Thoracic Aortic Disease. Cardiogenetics 2021, 11, 132-138. https://doi.org/10.3390/cardiogenetics11030015

AMA Style

Bhave SA, Guo D, Angelov SN, Bamshad MJ, Nickerson DA, Milewicz DM, Wallingford MC. Human SMAD4 Genomic Variants Identified in Individuals with Heritable and Early-Onset Thoracic Aortic Disease. Cardiogenetics. 2021; 11(3):132-138. https://doi.org/10.3390/cardiogenetics11030015

Chicago/Turabian Style

Bhave, Shreyas A., Dongchuan Guo, Stoyan N. Angelov, Michael J. Bamshad, Deborah A. Nickerson, Dianna M. Milewicz, and Mary C. Wallingford 2021. "Human SMAD4 Genomic Variants Identified in Individuals with Heritable and Early-Onset Thoracic Aortic Disease" Cardiogenetics 11, no. 3: 132-138. https://doi.org/10.3390/cardiogenetics11030015

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