Comparative Risks of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease.

Background: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.

Objectives: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.

Methods: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, and location of recruitment.

Expanding ACTA2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome.

Pathogenic variants in ACTA2, encoding smooth muscle α-actin, predispose to thoracic aortic aneurysms and dissections. ACTA2 variants altering arginine 179 predispose to a more severe, multisystemic disease termed smooth muscle dysfunction syndrome (SMDS; OMIM 613834). Vascular complications of SMDS include patent ductus arteriosus (PDA) or aortopulmonary window, early-onset thoracic aortic disease (TAD), moyamoya-like cerebrovascular disease, and primary pulmonary hypertension.

Update on the genetic risk for thoracic aortic aneurysms and acute aortic dissections: implications for clinical care.

Genetic variation plays a significant role in predisposing individuals to thoracic aortic aneurysms and dissections. Advances in genomic research have led to the discovery of 11 genes validated to cause heritable thoracic aortic disease (HTAD). Identifying the pathogenic variants responsible for aortic disease in affected patients confers substantial clinical utility by establishing a definitive diagnosis to inform tailored treatment and management, and enables identification of at-risk relatives to prevent downstream morbidity and mortality.

Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.

Background: Bicuspid aortic valve (BAV) is the most common cardiovascular malformation in adults, with a prevalence of 0.5%-2%. The prevalence of BAV in cohorts who were ascertained due to thoracic aortic aneurysms or acute aortic dissections (TAD) is as high as 20%.

The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.

Purpose: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

Methods: Exome sequencing from 39 trios were analyzed.

MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants.

Purpose: Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited.

Methods: Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed.

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.

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.

Genetic Variants in LRP1 and ULK4 Are Associated with Acute Aortic Dissections.

Acute aortic dissections are a preventable cause of sudden death if individuals at risk are identified and surgically repaired in a non-emergency setting. Although mutations in single genes can be used to identify at-risk individuals, the majority of dissection case subjects do not have evidence of a single gene disorder, but rather have the other major risk factor for dissections, hypertension. Initial genome-wide association studies (GWASs) identified SNPs at the FBN1 locus associated with both thoracic aortic aneurysms and dissections.

LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.

Rationale: Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75% of families.

Objectives: To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections.

Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene.

Almost one-quarter of patients presenting with thoracic aortic aneurysms (TAAs) or acute aortic dissections (TAADs) have an underlying mutation in a specific gene. A subset of these patients will have systemic syndromic features, for example, skeletal features in patients with Marfan Syndrome. It is important to note that the majority of patients with thoracic aortic disease will not have these syndromic features but many will have a family history of the disease.