Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms.

A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.

Familial thoracic aortic aneurysms and dissections: identification of a novel locus for stable aneurysms with a low risk for progression to aortic dissection.

Background: Thoracic aortic aneurysms leading to acute aortic dissections are the major diseases that affect the thoracic aorta. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of TAAD, and these patients present younger with more rapidly enlarging aneurysms than patients without a family history of aortic disease.

Methods And Results: A large family with multiple members with TAAD inherited in an autosomal-dominant manner was identified.

TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections.

Aims: Transforming growth factor-β (TGF-β) signaling is critical for the differentiation of smooth muscle cells (SMCs) into quiescent cells expressing a full repertoire of contractile proteins. Heterozygous mutations in TGF-β receptor type II (TGFBR2) disrupt TGF-β signaling and lead to genetic conditions that predispose to thoracic aortic aneurysms and dissections (TAADs). The aim of this study is to determine the molecular mechanism by which TGFBR2 mutations cause TAADs.

Paucity of skeletal manifestations in Hispanic families with FBN1 mutations.

Marfan syndrome (MFS) is an autosomal dominant condition with pleiotropic manifestations involving the skeletal, ocular, and cardiovascular systems. The diagnosis is based primarily on clinical involvement of these and other systems, referred to as the Ghent criteria. We have identified three Hispanic families from Mexico with cardiovascular and ocular manifestations due to novel FBN1 mutations but with paucity of skeletal features.

Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease.

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD.

An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease.

Marfan syndrome (MFS) results from heterozygous mutations in FBN1. However, genetic analyses of deoxyribonucleic acid (DNA) from approximately 10-30% of MFS patients who meet diagnostic criteria do not reveal an identifiable FBN1 mutation. In a patient who met the diagnostic criteria for MFS, bidirectional DNA sequencing of exons and intron-exon boundaries of FBN1 failed to reveal a mutation.

Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction.

Thoracic aortic aneurysms leading to type A dissections (TAAD) can be inherited in isolation or in association with genetic syndromes, such as Marfan syndrome and Loeys-Dietz syndrome. When TAAD occurs in the absence of syndromic features, it is inherited in an autosomal dominant manner with decreased penetrance and variable expression, the disease is referred to as familial TAAD. Familial TAAD exhibits significant clinical and genetic heterogeneity.

Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD).

MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II.

Non-syndromic thoracic aortic aneurysms and dissections (TAADs) are inherited in an autosomal dominant manner in approximately 20% of cases. Familial TAAD is genetically heterogeneous and four loci have been mapped for this disease to date, including a locus at 16p for TAAD associated with patent ductus arteriosus (PDA). The defective gene at the 16p locus has recently been identified as the smooth muscle cell (SMC)-specific myosin heavy chain gene (MYH11).

Severe aortic and arterial aneurysms associated with a TGFBR2 mutation.

Background: A 24-year-old man presented with previously diagnosed Marfan's syndrome. Since the age of 9 years, he had undergone eight cardiovascular procedures to treat rapidly progressive aneurysms, dissection and tortuous vascular disease involving the aortic root and arch, the thoracoabdominal aorta, and brachiocephalic, vertebral, internal thoracic and superior mesenteric arteries. Throughout this extensive series of cardiovascular surgical repairs, he recovered without stroke, paraplegia or renal impairment.

Genetic basis of thoracic aortic aneurysms and dissections: potential relevance to abdominal aortic aneurysms.

Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) have long been known to occur in association with a genetic syndrome such as Marfan syndrome (MFS). More recently, TAAD has also been demonstrated to occur as an autosomal dominant disorder in the absence of syndromic features, termed familial TAAD. Familial TAAD demonstrates genetic heterogeneity, and linkage studies have identified TAAD loci at 5q13-14 (TAAD1), 11q23 (FAA1), 3p24-25 (TAAD2), and 16p12.

Familial thoracic aortic aneurysms and dissections: three families with early-onset ascending and descending aortic dissections in women.

Ascending thoracic aortic aneurysms leading to type A dissections can be inherited in an autosomal dominant manner with variable age of onset and decreased penetrance, primarily in women. Three families are described with autosomal dominant inheritance of either ascending aortic aneurysms leading to type A dissections or type B dissections, and a young age of onset of aortic dissections in both men and women. Pedigree analysis suggests that a de novo mutation is responsible for the disease in one family.

Genetic basis of thoracic aortic aneurysms and aortic dissections.

Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) can occur in association with a genetic syndrome, such as Marfan syndrome (MFS), or as an autosomal dominant disorder in the absence of syndromic features, termed familial TAAD. Familial TAAD demonstrates genetic heterogeneity, and linkage studies have identified three TAAD loci at 5q13-14 (TAAD1), 11q23 (FAA1), and 3p24-25 (TAAD2). The underlying genetic heterogeneity of TAAD is reflected in the phenotypic variation associated with familial TAAD with respect to age of onset, progression, penetrance, and association with additional cardiac and vascular features.

Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections.

Background: A genetic predisposition for progressive enlargement of thoracic aortic aneurysms leading to type A dissection (TAAD) is inherited in an autosomal-dominant manner in up to 19% of patients, and a number of chromosomal loci have been identified for the condition. Having mapped a TAAD locus to 3p24-25, we sequenced the gene for transforming growth factor-beta receptor type II (TGFBR2) to determine whether mutations in this gene resulted in familial TAAD.

Methods And Results: We sequenced all 8 coding exons of TGFBR2 by using genomic DNA from 80 unrelated familial TAAD cases.