• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Thoracic Aortic Aneurysms and Aortic Dissections

Includes: ACTA2-Related Thoracic Aortic Aneurysms and Aortic Dissections, FBN1-Related Thoracic Aortic Aneurysms and Aortic Dissections, MYH11-Related Thoracic Aortic Aneurysms and Aortic Dissections, MYLK- Related Thoracic Aortic Aneurysms and Aortic Dissections, SMAD3- Related Thoracic Aortic Aneurysms and Aortic Dissections, TGFBR1-Related Thoracic Aortic Aneurysms and Aortic Dissections, TGFBR2-Related Thoracic Aortic Aneurysms and Aortic Dissections

, MD, PhD and , MS, CGC.

Author Information
, MD, PhD
Division of Medical Genetics
Department of Internal Medicine
University of Texas Medical School at Houston
Houston, Texas
, MS, CGC
Division of Medical Genetics
Department of Internal Medicine
University of Texas Medical School at Houston
Houston, Texas

Initial Posting: ; Last Revision: January 12, 2012.

Summary

Disease characteristics. The major cardiovascular manifestations of thoracic aortic aneurysms and aortic dissections (TAAD) include: (1) dilatation of the ascending thoracic aorta at the level of the sinuses of Valsalva or ascending aorta or both; and (2) dissections of the thoracic aorta involving either the ascending (Stanford type A dissections) or descending aorta (Stanford type B). Rarely an aneurysm involving the descending thoracic aorta is observed. Vascular manifestations can be the only findings. In the absence of surgical repair of the ascending aorta, affected individuals typically have progressive enlargement of the ascending aorta leading to an acute aortic dissection. The age of onset and presentation of the aortic disease are highly variable, as are the other vascular diseases and features associated with the aortic disease.

Diagnosis/testing. TAAD is diagnosed using different imaging modalities such as echocardiography, computed tomography (CT), magnetic resonance imaging (MRI), or angiography. Up to 20% of individuals with TAAD have a first-degree relative with thoracic aortic disease. Familial TAAD (FTAAD) is diagnosed based on the presence of dilatation and/or dissection of the thoracic aorta, absence of clinical features of Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome, and presence of a positive family history of TAAD. TGFBR2, TGFBR1, MYH11, ACTA2, MYLK, SMAD3, and two loci on other chromosomes, AAT1 (FAA1) and AAT2 (TAAD1), are associated with familial TAAD. Rarely, FTAAD can also be caused by FBN1 mutations. Further locus heterogeneity is evident: to date, only about 20% of familial TAAD is accounted for by mutations in known genes.

Management. Treatment of manifestations: Medications that reduce hemodynamic stress on the aorta, such as beta adrenergic blocking agents, are recommended. When the rate of dilation of the ascending aorta approaches 0.5 cm per year or the diameter is between 4.2 and 5.0 cm (depending on the underlying mutation or family history), elective repair of the ascending aorta is recommended to prevent a life-threatening aortic dissection or rupture. Early prophylactic repair should be considered in individuals with confirmed mutations in TGFBR2 and TGFBR1 and/or a family history of aortic dissection with minimal aortic enlargement.

Surveillance: Appropriate imaging studies (echocardiography, CT, or MRI) should be performed at frequent intervals to monitor the status of the affected segment of the thoracic aorta. Imaging for additional vascular diseases is based on the gene that is mutated and/or family history.

Agents/circumstances to avoid: Uncontrolled hypertension, smoking, isometric exercise, bodybuilding/weight training exercises, and competitive sports that could lead to a significant blow to the chest should be avoided.

Evaluation of relatives at risk: Aortic imaging is recommended for first-degree relatives of individuals with TAAD. Because of the variability of age of onset of TAAD, aortic imaging once a year or every few years is warranted for at-risk relatives in families with inherited or familial TAAD. If the disease-causing mutation is known, genetic counseling and testing of at-risk first-degree relatives assures that only relatives with the familial mutation undergo aortic imaging.

Genetic counseling. Familial TAAD is primarily inherited in an autosomal dominant manner with variable expression and decreased penetrance. The majority of individuals with familial TAAD have an affected parent. The children of an affected parent have an up to 50% chance of inheriting the genetic predisposition to TAAD. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

Diagnostic criteria. The major diagnostic criteria for familial thoracic aortic aneurysms and aortic dissections are the following:

  • Progressive enlargement of the ascending thoracic aorta involving the sinuses of Valsalva, the ascending aorta, or both. Individuals with a bicuspid aortic valve (BAV) may initially have dilatation either of the ascending aorta distal to the sinuses of Valsalva [Hahn et al 1992] or of the sinuses of Valsalva.

    The diagnosis of preaneurysmal dilatation of the proximal aortic root or ascending aorta is based on measurement of the dimensions of the sinuses of Valsalva and ascending aorta using imaging modalities such as 2D echocardiography, CT scan, MRI, or angiography and comparison with age-appropriate nomograms indexed for body surface area (BSA) [Roman et al 1993]. It is recommended that the following four sites of the ascending thoracic aorta be measured to best compare serial measurements: (1) annulus; (2) mid-sinuses of Valsalva; (3) supraaortic ridge or sinotubular junction; and (4) proximal ascending aorta.

    Note: (1) Aortic root measurement often underestimates the true dimensions at the sinuses of Valsalva. (2) In families in which aneurysms involve the ascending aorta, CT or MRI may be required for accurate assessment because echocardiography may not clearly define the diameter of the ascending aorta.
  • A positive family history of TAAD

Molecular Genetic Testing

Genes. Seven genes and two loci are known to be associated with TAAD:

Other loci. Linkage mapping studies demonstrate additional genetic heterogeneity for familial TAAD.

Clinical testing

  • Sequence analysis

    TGFBR1. Missense mutations in the kinase domain of TGFBR1 have been observed in individuals with familial TAAD.

    TGFBR2. In five unrelated families, TGFBR2 mutations leading to familial TAAD altered the arginine at codon 460 in the receptor to either cysteine or histidine. See Table 2. Mutations that result in disruption of amino acids other than Arg460 in the kinase domain have been observed in persons with familial TAAD.

    ACTA2. Various missense mutations have been identified in individuals with TAAD and account for 10-14% of FTAAD.

    FBN1. Mutations in FBN1 cause the Marfan syndrome characterized by skeletal, ocular, and cardiovascular manifestations. FBN1 mutations have also been identified in individuals and families with isolated thoracic aortic aneurysm and dissection [Milewicz et al 1996, Katzke et al 2002, Körkkö et al 2002, Stheneur et al 2009]. Although it has not been rigorously assessed, current data suggest that FBN1 mutations are a rare cause of isolated or family thoracic aortic disease.

    MYH11. Two splicing and one missense mutation in the c-terminal coiled-coil region of MYH11 have been described in two families with TAAD and patent ductus arteriosus (PDA) [Zhu et al 2006]. In all families reported with familial TAAD and a MYH11 mutation, PDA was present in one or more affected family members.

    MYLK. One nonsense and four missense variants were identified in MYLK in unrelated probands with FTAAD. Two MYLK alterations, p.Arg1480X (c.4438C>T) and p.Ser1759Pro (c.5275T>C), segregated with TAAD in two families. Familial segregation of the other variants was not confirmed due to lack of additional family members for analysis [Wang et al 2010].

    SMAD3. A frameshift mutation in exon 5 and three missense mutations in exons 2 and 6 of SMAD3 have been reported in families with TAAD, intracranial and other arterial aneurysms. SMAD3 mutations in exon 6 have also been reported in patients with the aneurysms osteoarthritis syndrome [Regalado et al 2011, van de Laar et al 2011].

Table 1. Summary of Molecular Genetic Testing Used in Familial Thoracic Aortic Aneurysms and Aortic Dissections

Gene SymbolProportion of TAAD Attributed to Mutations in This Gene 1Test MethodMutations Detected
TGFBR11%Sequence analysisSequence variants 3
Deletion/duplication analysis 4Partial- or whole-gene deletions/ duplications
TGFBR24%Sequence analysisSequence variants 3
Deletion/duplication analysis 4Partial- or whole-gene deletions / duplications
MYH11~1%Sequence analysisSequence variants 3, 5
Deletion/duplication analysis 4Partial- or whole-gene deletions / duplications
ACTA210%-14% 6Sequence analysisSequence variants 3
Deletion/duplication analysis 4Partial- or whole-gene deletions / duplications
FBN1UnknownSequence analysisSequence variants 3
Deletion/duplication analysis 4Partial- or whole-gene deletions / duplications
MYLK~1% Sequence analysisSequence variants 3
SMAD32%Sequence analysisSequence variants 3

1. Data are based on results of sequence analysis only, not other molecular genetic test methods.

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

5. Numerous nonsynonymous rare variants have been identified in MYH11 in persons with vascular diseases; the clinical significance of these variants is not known.

6. Guo et al [2007]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing of ACTA2 is a reasonable first step when attempting to determine the underlying cause of familial TAAD.

Sequencing of the other seven genes in which a mutation is known to cause familial TAAD (TGFBR1, TGFBR2, MYH11, FBN1, MYLK, and SMAD3) may be considered in individuals with familial TAAD who do not have an ACTA2 mutation or who have other clinical findings associated with mutations in these genes (see Clinical Description).

Multi-gene panel. An alternative to the sequential molecular genetic testing described above is a panel in which some or all of the genes that cause Marfan syndrome/ Loeys-Dietz syndrome/ familial thoracic aortic aneurysms and dissections are sequenced simultaneously. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual also varies. Note: Typically, mutation(s) identified by such a panel are confirmed by the testing laboratory using a different technology.

Predictive testing for at-risk family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The natural history of ascending aortic aneurysms that have not been surgically repaired is progressive enlargement over time and ultimately acute aortic dissection or, rarely, aortic rupture. Thoracic aortic aneurysms tend to be asymptomatic and may not be diagnosed until a catastrophic acute aortic dissection occurs. Aortic dissection occurs when the blood in the aortic lumen enters the wall of the aorta through an intimal tear and dissects along the plane of the aortic wall creating a false lumen. Aortic dissections originate primarily in the ascending aorta just above the aortic valve (ascending or Stanford type A dissection), but can also occur in the descending thoracic aorta just distal to the origin of the left subclavian artery (descending or Stanford type B). Although enlargement of the aorta typically precedes dissection, data from the International Registry of Aortic Dissections (IRAD) indicate that nearly 60% of ascending aortic aneurysms dissect at aortic diameters of less than 5.5 cm [Milewicz et al 1998, Pape et al 2007].

As an aortic aneurysm enlarges, the aortic annulus can become stretched, leading to secondary aortic regurgitation.

Pain is the most common symptom of an aortic dissection. Pain is usually abrupt in onset and severe in intensity, and is described as sharp or stabbing. Severe pain usually occurs in the chest (front, back, or both), but occasionally in the abdomen when the tear involves the abdominal aorta. Dissections can also cause other signs and symptoms including pallor, pulselessness, paresthesia, stroke, acute myocardial infarction, and paralysis.

The age of onset and rate of progression of aortic dilatation is highly variable even within families. One family member may present with an aneurysm at a young age, whereas another may not present until an elderly age. The mean age of presentation of familial TAAD is earlier than for non-familial TAAD but later than for Marfan syndrome [Coady et al 1999, Albornoz et al 2006]. Aortic dissection is rare in early childhood and aortic dilatation may not be present in childhood. Aortic dissections have occurred in children with FTAAD as young as age 12 years.

In most adults, the risk of aortic dissection or rupture increases at a maximal aortic dimension of about 5.5 centimeters [Davies et al 2002]. However, aortic dissections have been reported in individuals with a TGFBR2 mutation at aortic diameters of less than 5.0 cm [Loeys et al 2005, Loeys et al 2006, Tran-Fadulu et al 2009]. Persons with a MYH11 or ACTA2 mutation have experienced aortic dissection at an aortic diameter of less than 5.5 cm [Guo et al 2007, Pannu et al 2007]. Families with multiple members who had aortic dissection with little to no aortic dilatation have also been reported [Milewicz et al 1998].

A minority of affected individuals may present with dissection of the descending aorta; furthermore it does not appear that dilation of the descending aorta precedes dissection in this location.

Life expectancy. With proper management, including medical therapy and prophylactic repair of an aneurysm (see Management), the life expectancy of an individual with a thoracic aortic aneurysm should approach that of the general population. At-risk family members who are screened for aortic dilatation and undergo prophylactic aortic surgery are expected to have a better prognosis than relatives ascertained at the time of aortic dissection.

Other manifestations. Although in TAAD, aneurysms, and dissections of the ascending thoracic aorta typically occur as an isolated cardiovascular abnormality without other phenotypic effects, associated features have been observed:

  • Aneurysms involving other arteries. Abdominal aortic aneurysms (AAA) as well as cerebral and peripheral artery aneurysms have been observed in families with TAAD: approximately 12% of families have AAAs, 9%-14% of families cerebral aneurysms, and 5% of families iliac or popliteal aneurysms [Authors, personal observation].

    Mutation of TGFBR1 or TGFBR2 has been excluded as the cause of associated aneurysms in the families described. Of note, in families with aTGFBR2 or TGFBR1 mutation, affected family members usually present with aortic disease, but the risk for aneurysms and dissections of other vessels including cerebral arteries is increased. Similarly, other arterial aneurysms (brain, iliac, abdominal aorta) have been observed in individuals with SMAD3 mutations.
  • Patent ductus arteriosus (PDA). Mutations in MYH11 have been identified in four families with TAAD in whom the TAAD was associated with PDA in some family members [Glancy et al 2001, Khau Van Kien et al 2004, Khau Van Kien et al 2005, Zhu et al 2006, Pannu et al 2007]. In addition, some ACTA2 mutations are associated with PDA [Guo et al 2009, Milewicz et al 2010].
  • Bicuspid aortic valve (BAV). Families with multiple members with BAV, TAAD, or BAV with TAAD have been reported [Loscalzo et al 2007].
  • Livedo reticularis, a purplish skin discoloration in a network pattern caused by constriction or occlusion of deep dermal capillaries, is observed in some, but not all, individuals with an ACTA2 mutation. In families with TAAD resulting from ACTA2 mutations associated with marked and persistent livedo reticularis, the skin rash can be used as a clinical marker of family members who have the mutation [Guo et al 2007].
  • Iris flocculi, an ocular abnormality previously described in individuals with familial TAAD, is associated with ACTA2 mutations [Lewis & Merin 1995, Guo et al 2007]. The presence of iris flocculi associated with TAAD should raise the possibility of an ACTA2 mutation.
  • Early onset occlusive vascular diseases. ACTA2 mutations can also cause early onset vascular occlusive disease, including coronary artery disease and stroke, as well as Moyamoya-like cerebrovascular disease with bilateral occlusion of the distal internal carotid artery typically accompanied with bilateral fusiform dilatation of the carotid artery proximal to the occlusion [Guo et al 2009, Milewicz et al 2010].

Pathology. A pathologic finding in the aorta in TAAD is the poorly understood lesion referred to as medial degeneration (previously termed Erdheim's cystic medial necrosis). The aortas inMarfan syndrome also show medial degenration. Features include degeneration of the aortic media characterized by fragmentation and loss of elastic fibers and accumulation of mucoid material. Although focal areas of smooth muscle cell loss in the aortic media with medial degeneration are observed, it is debated whether there is overall loss or gain of smooth muscle cells in the aortic media [Tang et al 2005].

Mutations in ACTA2 and MYH11 are also associated with the pathologic findings of medial degeneration as well as localized areas of increased numbers of smooth muscle cells and smooth muscle cell disarray reminiscent of the myocyte disarray observed in hypertrophic cardiomyopathy [Guo et al 2007, Pannu et al 2007]. Mutations in these genes are also associated with medial thickening of the arteries in the vasa vasorum in the adventitial layer of the aorta.

Genotype-Phenotype Correlations

TGFBR2. In most adults, the risk for aortic dissection or rupture becomes significant when the maximal aortic dimension reaches about 5.5 cm; however, in individuals with TGFBR2 mutations, dissection of the aorta may occur before the aorta enlarges to 5.0 cm.

The majority of individuals with TAAD resulting from TGFBR2 mutations present initially with aortic disease; however, there is increased risk for aneurysms and dissections of other vessels, including cerebral aneurysms [Loeys et al 2005, Loeys et al 2006, LeMaire et al 2007, Tran-Fadulu et al 2009].

MYH11. Mutations in MYH11 have been identified in two families with TAAD in whom the TAAD was associated with patent ductus arteriosus (PDA) in some family members [Glancy et al 2001, Khau Van Kien et al 2004, Khau Van Kien et al 2005, Zhu et al 2006].

ACTA2. Features associated with ACTA2 mutations include livedo reticularis and iris flocculi although the prevalence of these features in persons with an ACTA2 mutation has not been determined. In some families, PDA and BAV are also present in ACTA2 mutation-positive individuals.

Genotype-phenotype correlations have emerged based on initial data from ACTA2 families indicating that the Arg258 change predisposes to TAAD and premature stroke, whereas other mutations (Arg149 and Arg118) predispose to TAAD and coronary artery disease [Guo et al 2009]. Furthermore, a subset of ACTA2 mutations also predisposes to Moyamoya disease, a rare cerebrovascular syndrome characterized by bilateral occlusion or stenosis of the terminal internal carotid arteries and the formation of collateral vessel networks at the base of the brain, so-called “moyamoya vessels.”

A recurrent de novo ACTA2 mutation, c.536G>A (Arg179His), and other de novo mutations that alter Arg179, cause dysfunction of smooth muscle cells throughout the body, leading to more severe and highly penetrant vascular diseases that include TAAD, patent ductus arteriosus, stenosis and dilatation of cerebral vessels, periventricular white matter hyperintensities on MRI, pulmonary hypertension, as well as fixed dilated pupils, hypotonic bladder, and malrotation and hypo-peristalsis of the gut [Milewicz et al 2010, unpublished data].

MYLK. Preliminary data indicate that MYLK mutations identified cause early aortic dissections with minimal or no dilatation [Wang et al 2010]. Phenotype-genotype correlations have not been delineated.

SMAD3. Phenotype-genotype correlations have not been delineated.

AAT1 locus. Affected individuals in one family with TAAD linked to this locus had dilatation of other segments of the aorta and other arteries [Vaughan et al 2001].

Penetrance

Family studies suggest penetrance is reduced, primarily in women, as demonstrated in families linked to the AAT2 locus [Guo et al 2001]. Reduced penetrance is also observed in families with mutations in ACTA2, MYH11, TGFBR1, TGFBR2, MYLK, and SMAD3.

Affected individuals in the one family with FTAAD linked to the AAT1 locus showed full penetrance for aneurysms or dissections of the aorta.

Prevalence

Aortic aneurysms, dissections and rupture have ranked as high as the 15th major cause of death in the United States, accounting for nearly 15,000 deaths annually [Hoyert et al 2001].

Family studies demonstrate that up to 19% of persons with TAAD without a known genetic syndrome have a first-degree relative with TAAD [Biddinger et al 1997, Coady et al 1999, Albornoz et al 2006].

Predisposition to TAAD is not known to be increased in any ethnic or racial group.

Differential Diagnosis

Marfan syndrome is a systemic disorder of the connective tissue involving the ocular, skeletal, and cardiovascular systems. Myopia is the most common ocular feature; displacement of the lens from the center of the pupil is seen in about 60% of affected individuals. Skeletal manifestations include joint laxity, disproportionately long extremities for the size of the trunk, pectus excavatum or pectus carinatum, and scoliosis. Cardiovascular manifestations include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, triscuspid valve prolapse, and enlargement of the proximal pulmonary artery. Mutations of FBN1 are causative. Inheritance is autosomal dominant.

Rarely, familial thoracic aortic aneurysm and aortic dissections (TAAD) results from FBN1 mutations. In these families, affected individuals do not have the ocular complications of Marfan syndrome and do not have sufficient skeletal features to fulfill the diagnostic criteria for Marfan syndrome [Francke et al 1995, Milewicz et al 1996].

Congenital contractural arachnodactyly (CCA) is characterized by a Marfan-like appearance with a tall, slender habitus in which arm span exceeds height and long, slender fingers and toes (arachnodactyly). At birth, most affected individuals have contractures of the major joints (knees and ankles) and the proximal interphalangeal joints of the fingers and toes (i.e., camptodactyly). Hip contractures, adducted thumbs, and club foot may occur. Contractures usually improve with time. Kyphosis/scoliosis, present in about half of all affected individuals, begins as early as infancy, is progressive, and causes the greatest morbidity in CCA. Dilatation of the aorta is present in some individuals and can progress over time [Gupta et al 2004]. Dilatation progressing to aortic dissection has not been reported. Mutations of FBN2 are causative. Inheritance is autosomal dominant.

Ehlers-Danlos syndrome, vascular type (EDS type IV). Cardinal features are thin, translucent skin, easy bruising, characteristic facial appearance, and arterial, intestinal, and/or uterine fragility. Affected individuals are at risk for arterial rupture, aneurysm, and/or dissection, gastrointestinal perforation or rupture, and uterine rupture during pregnancy. The diagnosis of EDS, vascular type is based on compatible clinical findings and confirmed by biochemical testing demonstrating the production of structurally abnormal collagen III by dermal fibroblasts or by molecular genetic testing demonstrating a mutation in COL3A1. Inheritance is autosomal dominant.

Loeys-Dietz syndrome. Features of this syndrome include cardiovascular abnormalities (aortic aneurysms, dissection and tortuousity; PDA), craniofacial abnormalities (including cleft palate, ocular hypertelorism, craniosynostosis, broad or bifid uvula), and skeletal abnormalities (arachnodactyly, dolichostenomelia, pectus deformity, camptodactyly, scoliosis, and joint laxity). The diagnosis of Loeys-Dietz syndrome can be confirmed through identification of a mutation in TGFBR2 or TGFBR1. Inheritance is autosomal dominant.

Abdominal aortic aneurysm (AAA). Abdominal aortic aneurysms typically involve the abdominal aorta below the renal arteries. The pathology associated with AAAs is consistent with atherosclerosis and not the medial degeneration observed in familial TAAD and Marfan syndrome. These aneurysms occur primarily in elderly men. Familial aggregation of these aneurysms is well established and first-degree relatives of an individual with AAAs have a twelvefold increased risk of developing AAAs [Tilson & Seashore 1984]. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms at loci that confer a slightly increased the risk for AAAs but no Mendelian genes have been identified [Helgadottir et al 2008, Gretarsdottir et al 2010].

Aneurysms-osteoarthritis syndrome (AOS). SMAD3 testing should be considered in individuals and families with TAAD and other features of the AOS, including arterial tortuosity and aneurysms, osteoarthritis, mild craniofacial, skeletal and cutaneous features as described previously [van de Laar et al 2011].

Multisystemic smooth muscle dysfunction syndrome. A recurrent de novo ACTA2 mutation, Arg179His, causes dysfunction of smooth muscle cells throughout the body, leading to more severe and highly penetrant vascular diseases that include TAAD, patent ductus arteriosus, stenosis and dilatation of cerebral vessels, periventricular white matter hyperintensities on MRI, pulmonary hypertension, as well as fixed dilated pupils, hypotonic bladder, and malrotation and hypo-peristalsis of the gut [Milewicz et al 2010].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with thoracic aortic aneurysms and aortic dissections (TAAD), the following evaluations are recommended:

  • Echocardiography to assess the diameters of the aortic root and ascending aorta and the structure and competence of the aortic valve. Imaging of the aorta by CT or MRI should be considered if the ascending aorta is not well visualized by echocardiography.
  • Imaging of the entire aorta or cerebrovascular arteries should be considered at the time of diagnosis, especially if there is a family history of vascular disease beyond the ascending thoracic aorta that involves these arteries.
  • Additional imaging in individuals with a TGFBR2, TGFBR1 or SMAD3 mutation is recommended, including imaging of the cerebral circulation, descending thoracic and abdominal aorta, and arterial branches originating from the aorta.
  • In addition to aortic imaging, cerebrovascular imaging to assess for cerebrovascular disease and cardiac evaluation to assess for coronary artery disease should be considered in individuals with an ACTA2 mutation.

Treatment of Manifestations

Management of thoracic aortic aneurysm and/or dissection requires coordinated input from a multidisciplinary team of specialists familiar with this condition, including a medical geneticist, cardiologist, and cardiothoracic surgeon.

Medical treatment to reduce hemodynamic stress, such as beta adrenergic-blocking agents, is routinely advised for individuals with the Marfan syndrome; similar treatment is recommended for individuals with familial TAAD [Shores et al 1994, Hiratzka et al 2010]. Because aortic dilatation may be present in childhood, medical therapy should be considered in children as well as adults with aortic dilatation.

Hypertension should be aggressively treated and controlled in individuals with familial TAAD, including individuals with aneurysms and those at risk of developing aneurysms. Other cardiovascular risk factors including smoking and hyperlipidemia should be addressed.

Prophylactic surgical repair of the aorta to prevent subsequent dissection or rupture is indicated in any of the following situations [Hiratzka et al 2010]:

  • For individuals with a confirmed TGFBR1 or TGFBR2 mutation, when the diameter of the ascending aorta reaches 4.2 cm by transesophageal echocardiogram (internal diameter) or 4.4 to 4.6 cm or greater by CT or MR imaging (external diameter)
  • For individuals with familial TAAD and/or a confirmed mutation in MYH11 or ACTA2, when the diameter of the ascending aorta is between 4.5 and 5.0 cm
  • For individuals with familial TAAD, when other relatives have experienced aortic dissection with documented minimal enlargement of the aortic diameter
  • For all others with TAAD, when the ascending aorta or aortic root reaches 5.0 cm, when the rate of dilatation is more than 0.5 cm per year, and/or when severe aortic stenosis or regurgitation is present

The Bentall procedure (aortic graft repair plus insertion of an aortic mechanical valve) was previously the most common surgical repair of an ascending aortic root aneurysm [Gott et al 1999]. More recently, a valve-sparing procedure that precludes the need for the chronic anticoagulation required following insertion of a mechanical aortic valve has been used [David et al 1999, Hiratzka et al 2010].

Surveillance

Appropriate imaging (echocardiography, CT, or MR) of the aorta should be performed at frequent intervals to monitor the status of the enlarged or dissected thoracic aorta.

After diagnosis of an aortic aneurysm, the imaging study should be repeated in six months to assess for any increase in aortic size and then yearly thereafter if the size remains stable. More frequent examinations are indicated if the ascending aorta and/or the aortic root exceed about 4.5 cm in an adult.

Depending on the gene that is mutated in a family, periodic imaging of the rest of the arterial tree including cerebral vessels should be performed.

  • For individuals with an ACTA2 mutation, screening for coronary artery disease and cerebrovascular disease is reasonable.
  • For individuals with a TGFBR1, TGFBR2, or SMAD3 mutation, annual imaging of the aorta and its branches and cerebrovascular circulation is recommended.

After repair of the ascending aorta, the remaining portion of the aorta needs to be routinely imaged for enlargement of the distal aorta, whether the individual had a Stanford type A dissection initially or underwent prophylactic repair of the ascending aorta.

Agents/Circumstances to Avoid

Isometric exercise and competitive sports that could lead to significant blows to the chest should be avoided as these could accelerate aortic root dilatation or cause dissection/rupture.

Evaluation of Relatives at Risk

If the family-specific mutation is known, family members at risk can be offered molecular genetic testing to clarify their genetic status so that those known to be heterozygous for a pathologic mutation can be monitored appropriately (see Surveillance).

Family members at risk of inheriting the genetic predisposition for TAAD should have baseline imaging of the ascending thoracic aorta by echocardiogram, CT, or MR. The variable age of onset of the aortic disease in familial TAAD makes it necessary to begin imaging the aorta of individuals at risk at a relatively young age. The authors recommend that imaging begin when a child can undergo an echocardiogram without sedation (usually age 6-7 years) unless onset in the family has been at a younger age. At-risk relatives should be monitored once every few years for aortic abnormalities if the initial assessment is normal [Hiratzka et al 2010]; repeat surveillance is indicated for those found to have aortic dilatation.

Because penetrance may be reduced in TAAD, it is appropriate to image first-degree relatives of an individual with familial TAAD whether that individual is the parent, sib, or offspring of the proband.

Imaging of the sons of women who are at a 50% risk of inheriting the disease-causing mutation but have normal aortic measurements, should be considered because of the decreased penetrance of TAAD in women [Pannu et al 2005, Tran-Fadulu et al 2009].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women with a thoracic aortic aneurysm are at increased risk for complications such as rapid aortic root enlargement and aortic dissection or rupture during pregnancy, delivery, or the post-partum period. Data obtained from women with Marfan syndrome indicate a high risk for aortic dissection when the aortic root diameter exceeds 4.0 cm [Rossiter et al 1995]. Women with TAAD should therefore be counseled about the risk for aortic dissection with pregnancy and inheritance of the disease and potential risk to offspring [Hiratzka et al 2010].

It is recommended that pregnant women with a known aortic root or ascending thoracic dilatation be monitored during pregnancy and postpartum by a cardiologist and a high-risk obstetrician, and undergo monthly or bimonthly echocardiographic assessment of the ascending aorta. It is recommended that pregnant women found to have dilatation of the aortic arch, descending thoracic aorta, or the abdominal aorta undergo MRI or transesophageal echocardiogram.

Pregnant women with thoracic aortic aneurysms should be delivered in centers where cardiothoracic surgery is available [Hiratzka et al 2010].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Familial thoracic aortic aneurysm and aortic dissection (TAAD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The majority of individuals diagnosed with familial TAAD have an affected parent.
  • It is appropriate to evaluate both parents for manifestations of thoracic aortic aneurysms by performing a comprehensive clinical examination and imaging of the sinuses of Valsalva, ascending aorta, and cardiac valves.

Sibs of a proband

  • The risk to the sibs of the proband depends on the status of the parents.
  • If a parent is affected, the risk to the sib of inheriting the disease-causing mutation is 50%; however, because of reduced penetrance, the likelihood that the sib will develop TAAD is slightly reduced, with increasing risk as the individual ages.
  • If there are other affected individuals in the extended family, reduced penetrance and variable expression of the disease raise the possibility that sibs could be at risk even if the parents are unaffected.

Offspring of a proband. The children of an affected parent are at a 50% risk of inheriting the mutant allele and the disorder. Since the penetrance of TAAD is reduced, offspring who inherit a mutant allele from a parent may or may not develop thoracic aortic aneurysms.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents, siblings, and offspring. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination in the first two trimesters is insensitive in detecting manifestations of thoracic aortic aneurysm.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Heart Association (AHA)
    7272 Greenville Avenue
    Dallas TX 75231
    Phone: 800-242-8721 (toll-free)
    Email: review.personal.info@heart.org
  • National Marfan Foundation (NMF)
    22 Manhasset Avenue
    Port Washington NY 11050
    Phone: 800-862-7326 (toll-free); 516-883-8712
    Fax: 516-883-8040
    Email: staff@marfan.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Thoracic Aortic Aneurysms and Aortic Dissections: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Thoracic Aortic Aneurysms and Aortic Dissections (View All in OMIM)

102620ACTIN, ALPHA-2, SMOOTH MUSCLE, AORTA; ACTA2
132900AORTIC ANEURYSM, FAMILIAL THORACIC 4; AAT4
134797FIBRILLIN 1; FBN1
160745MYOSIN, HEAVY CHAIN 11, SMOOTH MUSCLE; MYH11
190181TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE I; TGFBR1
190182TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE II; TGFBR2
600922MYOSIN LIGHT CHAIN KINASE; MYLK
603109MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 3; SMAD3
607086AORTIC ANEURYSM, FAMILIAL THORACIC 1; AAT1
607087AORTIC ANEURYSM, FAMILIAL THORACIC 2; AAT2
611788AORTIC ANEURYSM, FAMILIAL THORACIC 6; AAT6
613780AORTIC ANEURYSM, FAMILIAL THORACIC 7; AAT7

TGFBR1

Normal allelic variants. The coding region of TGFBR1 consists of nine exons. No alternatively spliced transcripts have been identified.

Pathologic allelic variants. Four missense mutations that affect the kinase domain of TGFBR1, causing familial thoracic aortic aneurysm and aortic dissections (TAAD), have been described [Tran-Fadulu et al 2009]. Several missense mutations that cause syndromic TAAD in association with Loeys-Dietz syndrome or related syndromes have been described [Loeys et al 2005, Ades et al 2006, Loeys et al 2006, Mátyás et al 2006, Singh et al 2006].

Normal gene product. TGFBR1 is a ubiquitously expressed type I transmembrane receptor protein with serine-threonine kinase activity. TGFBR1 is recruited by TGFBR2 in response to TGFβ-binding and transduces the TGFβ signal intracellularly by recruitment and phosphorylation of SMAD proteins. TGFβ signaling plays an important role in cellular proliferation, differentiation, and extracellular matrix production.

Abnormal gene product. TGFBR1 mutations leading to aneurysms and dissections occur predominantly in the functionally important intraceullular kinase domain of the protein and are predicted to cause loss of function. However, evidence also suggests that the TGFβ pathway may be upregulated in aortic tissue from individuals with TGFBR1 mutations [Loeys et al 2005]. The precise function of the abnormal gene product is currently under investigation.

TGFBR2

Normal allelic variants. The coding region of TGFBR2 consists of eight exons. Two isoforms are transcribed from the gene as a result of alternative splicing of a coding exon located between the exons designated exon 1 and exon 2.

Pathologic allelic variants. Two recurrent missense mutations affecting the kinase domain that lead to familial TAAD have been described [Pannu et al 2005]. Mutations disrupting an amino acid other than p.Arg460 in the kinase domain have been observed in familial TAAD [Pannu, personal communication]. Several missense mutations that cause syndromic TAAD in association with Marfan syndrome, Loeys-Dietz syndrome, or related syndromes have been described [Mizuguchi et al 2004, Ki et al 2005, Loeys et al 2005, Ades et al 2006, Disabella et al 2006, Loeys et al 2006, Mátyás et al 2006, Singh et al 2006, LeMaire et al 2007].

Table 2. TGFBR2 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1378C>Tp.Arg460CysNM_003242​.5
NP_003233​.4
c.1379G>Ap.Arg460His

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. TGFBR2 is a ubiquitously expressed type II transmembrane receptor protein with serine-threonine kinase activity. TGFBR2 binds TGFβ and transduces the TGFβ signal intracellularly by recruitment and phosphorylation of the type I transmembrane receptor, TGFBR1. TGFβ signaling plays an important role in cellular proliferation, differentiation and extracellular matrix production.

Abnormal gene product. TGFBR2 mutations leading to aneurysms and dissections occur predominantly in the functionally important intracellular kinase domain and are predicted to cause loss of function. This has been demonstrated by functional analysis of mutant TGFBR2 in cell lines [Mizuguchi et al 2004, Inamoto et al 2010]. However, evidence also suggests that the TGFβ pathway may be upregulated in aortic tissue from individuals with TGFBR2 mutations [Loeys et al 2005]. The precise function of the abnormal gene product is currently under investigation.

MYH11

Normal allelic variants. The coding region of MYH11 consists of 41 exons. Four alternatively spliced transcripts are expressed in aortic smooth muscle cells, SM1A and B and SM2A and B. The NM_002474.2 reference sequence is transcript variant (SM1A).

Pathologic allelic variants. Heterozygous MYH11 mutations were identified in two families with familial thoracic aortic aneurysm and dissection with patent ductus arteriosus: a splice donor site mutation (IVS32+1G>T) and a missense mutation (5273G>A) on the same allele and a 72-nucleotide deletion in exon 28 (3810_3881del) [Zhu et al 2006]. See Table 3 (pdf). Two missense mutations, Leu1264Pro and Arg1275Leu, in the coiled-coil domain in one family and another missense mutation, Arg712Gln, in the MYH11 ATPase head region in an unrelated family have also been reported [Pannu et al 2007]. See Table 4.

Table 4. Selected MYH11 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.2135G>Ap.Arg712GlnNM_002474​.2
NP_002465​.1
c.3791T>Cp.Leu1264Pro
c.3824G>Tp.Arg1275Leu

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. MYH11 is the smooth muscle-specific isoform of the myosin heavy chain protein. Smooth muscle myosin, the major contractile protein in the thick filaments of the contractile units in these cells, is composed of a MYH11 dimer along with two pairs of non-identical light chains.

Abnormal gene product. Deletion and missense mutations located in the c-terminal domain of MYH11 are predicted to affect the structure and assembly of myosin thick filaments. Evidence suggests that mutant MYH11 acts in a dominant-negative manner by altering the stability of the coiled-coil structure in the rod region of the protein through its interaction with wild-type MYH11 [Zhu et al 2006].

ACTA2

Normal allelic variants. The coding region of ACTA2 consists of nine exons. No alternatively spliced transcripts are identified. No SNP is identified in the coding region of ACTA2.

Pathologic allelic variants. Over 20 ACTA2 missense mutations and mutations leading to exon splicing errors have been described in families with TAAD [Guo et al 2007, Guo et al 2009]. See Table 5 (pdf).

Table 6. Selected ACTA2 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.536G>Ap.Arg179His 1NM_001613​.2
NP_001604​.1

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. De novo recurrent mutation

Normal gene product. ACTA2, or smooth muscle alpha-actin, is a smooth muscle cell-specific protein. Alpha-actin is a major contractile protein in these cells and polymerization of α-actin forms the backbone of the thin filament of the sarcomere. The α-actin protein sequence is highly conserved from human to zebrafish.

Abnormal gene product. Missense mutations in ACTA2 are predicted to affect the structure and assembly of actin filaments. Protein structure analysis suggests that mutant α-actin acts in a dominant-negative manner by altering the ability of protein polymerization or ability of α-actin binding to regulatory proteins or nucleotide.

FBN1

Normal allelic variants. FBN1 is large (>600 kb) and the coding sequence is highly fragmented (65 exons). The promoter region is large and poorly characterized. High evolutionary conservation of intronic sequence at the 5' end of the gene suggests the presence of intronic regulatory elements. Three exons at the extreme 5' end of the gene are alternatively utilized and do not appear to contribute to the coding sequence.

Pathologic allelic variants. More than 200 FBN1 mutations that cause Marfan syndrome or related phenotypes have been described [Vollbrandt et al 2004]. No common mutation exists in any population. (For more information, see Table A.)

Normal gene product. Fibrillin-1 is an extracellular matrix protein that contributes to large structures called microfibrils. Microfibrils are found in both elastic and nonelastic tissues. They participate in the formation and homeostasis of the elastic matrix, in matrix-cell attachments, and possibly in the regulation of selected growth factors. Studies in animal models of Marfan syndrome have demonstrated that microfibrils regulate the matrix sequestration and activation of the growth factor TGFβ. Excess TGFβ signaling has been observed in the developing lung, the mitral valve, the skeletal muscle, the dura, and the ascending aorta [Neptune et al 2003, Ng et al 2004, Jones et al 2005, Loeys et al 2005, Habashi et al 2006, Cohn et al 2007]. TGFβ antagonism in vivo has been shown to attenuate or prevent pulmonary emphysema, myxomatous changes of the mitral valve, skeletal muscle myopathy, and progressive aortic enlargement seen in fibrillin-1-deficient mice. The relevance of this mechanism to other manifestations of Marfan syndrome is currently being explored. Other studies have highlighted the potential role of matrix-degrading enzymes in the pathogenesis of aortic disease in Marfan syndrome [Bunton et al 2001, Booms et al 2005].

Abnormal gene product. The pathogenesis of Marfan syndrome is complex. Mutant forms of fibrillin-1 are believed to have dominant-negative activity. That is, the mutant forms can interfere with the utilization of the normal protein derived from the opposite allele. A hallmark feature of the Marfan syndrome is a severe reduction of microfibrils in explanted tissues and in the matrix deposited by cultured dermal fibroblasts. The residual level of protein is generally far below the 50% level predicted by the presence of a wild-type copy of FBN1 in all affected individuals.

Marfan syndrome and related disorders can also be caused by premature termination codon mutations or gene deletions that reduce expression from the mutant allele. Thus, haploinsufficiency also contributes to the pathogenesis of disease. Animal studies suggest that half-normal amounts of fibrillin-1 (i.e., haploinsufficiency) may be insufficient to initiate productive microfibrillar assembly [Judge et al 2004]. Polymorphic variation regulating the output of the wild-type allele can contribute to the severity of disease in the haploinsufficient state [Hutchinson et al 2003].

MYLK

Normal allelic variants. The myosin light chain kinase (MLCK) is encoded by MYLK and it is reported that different isoforms of MLCK are encoded by differential use of the 31 coding exons [Watterson et al 1999]. The reference sequence NM_053025.3 has 34 total exons.

Pathologic allelic variants. One nonsense and four missense variants that were not present in matched controls were identified in MYLK. Two MYLK variants, c.4438C>T and c.5275T>C, segregated with TAAD in two families. Three additional MYLK variants were identified, c.5260G>A, c.3637G>A, and c.4195G>A, but additional affected family members were not available for segregation analysis.

Table 7. Selected MYLK Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.3637G>Ap.Val1213MetNM_053025​.3
NP_444253​.3
c.4195G>Ap.Glu1399Lys
c.4438C>Tp.Arg1480X
c.5260G>Ap.Ala1754Thr
c.5275T>Cp.Ser1759Pro

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. MYLK encodes three gene products expressed from separate promoters, with two isoforms containing the catalytic and CaM-binding domains (the 220-kd long form and the 130-kd short form, respectively) and a third, small, non-catalytic protein (NP_444259.1) called telokin. Telokin is a 17-kd protein that affects calcium sensitivity of contraction, primarily in intestinal smooth muscle. The myosin light chain kinase (MLCK) is a ubiquitously expressed kinase whose only target of phosphorylation is the 20-kd regulatory light chain (RLC) of smooth and non-muscle myosin II. MLCK is highly expressed in smooth muscle cells, where phosphorylation of RLC by MLCK initiates the physiologic contraction of smooth muscle cells in hollow organs.

Abnormal gene product. A c.4438C>T (p.Arg1480X) mutation located in the MLCK kinase domain leads to either nonsense-mediated decay or a truncated protein missing the kinase and CaM binding domains and therefore predicted to disrupt the kinase activity. Two other missense alterations, c.5260G>A and c.5275T>C, disrupt amino acids in the α-helix of the calmodulin-binding sequence and were demonstrated to lead to decreased MLCK function by disrupting CaM binding. In particular, the phosphorylation of the serine in position 1759 disrupts CaM binding and desensitizes MLCK to activation by calcium/CaM.

SMAD3

Normal allelic variants. Human SMAD3 consists of nine exons [Arai et al 1998]. There are several transcript variants (www.ncbi.nlm.nih.gov/gene/4088).

Pathologic allelic variants. One frameshift mutation and three missense mutations were identified in individuals with FTAAD, located in exons 2, 5, and 6 (Table 8). A frameshift mutation and two missense mutations were identified in exon 6 of SMAD3 in individuals with the aneurysms-osteoarthritis syndrome.

Table 8. Selected SMAD3 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeExonProtein Amino Acid ChangeReference Sequences
c.335C>T2p.Ala112ValNM_005902​.3
NP_005893​.1
c.652delA5p.Asn218Thrfs*23
c.715G>A6p.Glu239Lys
c.836G>A6p.Arg279Lys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. SMAD3 encodes a protein with conserved amino and carboxyl domains, MH1 and MH2, separated by a variable linker region. SMAD3 is a direct mediator of transcriptional activation by the TGF-β signaling pathway. TGF-β initiates cell signaling by binding to the type I and type II receptors on the cell surface (encoded by TGFBR1 and TGFBR2), inducing phosphorylation and activation of the type 1 receptor by the type 2 receptor. The type 1 receptor kinase then phosphorylates cytoplasmic substrates, SMAD2 and SMAD3. Once phosphorylated, these form homomeric and heteromeric complexes with SMAD4, which accumulate in the nucleus and regulate expression of target genes [Shi & Massagué 2003, Ross & Hill 2008].

Abnormal gene product. A frameshift mutation (c.652delA) in exon 5 was identified and predicted to lead to premature termination of protein translation and probably to nonsense-mediated decay of the RNA. A c.335C>T alteration was identified in exon 2 encoding the MH1 domain that is involved in DNA binding. Two additional mutations, c.715G>A and c.836G>A, were identified in exon 6 encoding the MH2 domain that is involved in protein-protein interactions [Regalado et al 2011]. These mutations are predicted to disrupt TGF-β signaling and transcription of target genes.

References

Literature Cited

  1. Ades LC, Sullivan K, Biggin A, Haan EA, Brett M, Holman KJ, Dixon J, Robertson S, Holmes AD, Rogers J, Bennetts B. FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited. Am J Med Genet A. 2006;140:1047–58. [PubMed: 16596670]
  2. Albornoz G, Coady MA, Roberts M, Davies RR, Tranquilli M, Rizzo JA, Elefteriades JA. Familial thoracic aortic aneurysms and dissections--incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg. 2006;82:1400–5. [PubMed: 16996941]
  3. Arai T, Akiyama Y, Okabe S, Ando M, Endo M, Yuasa Y. Genomic structure of the human Smad3 gene and its infrequent alterations in colorectal cancers. Cancer Lett. 1998;122:157–63. [PubMed: 9464505]
  4. Biddinger A, Rocklin M, Coselli J, Milewicz DM. Familial thoracic aortic dilatations and dissections: a case control study. J Vasc Surg. 1997;25:506–11. [PubMed: 9081132]
  5. Booms P, Pregla R, Ney A, Barthel F, Reinhardt DP, Pletschacher A, Mundlos S, Robinson PN. RGD-containing fibrillin-1 fragments upregulate matrix metalloproteinase expression in cell culture: a potential factor in the pathogenesis of the Marfan syndrome. Hum Genet. 2005;116:51–61. [PubMed: 15517394]
  6. Bunton TE, Biery NJ, Myers L, Gayraud B, Ramirez F, Dietz HC. Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome. Circ Res. 2001;88:37–43. [PubMed: 11139471]
  7. Coady MA, Davies RR, Roberts M, Goldstein LJ, Rogalski MJ, Rizzo JA, Hammond GL, Kopf GS, Elefteriades JA. Familial patterns of thoracic aortic aneurysms. Arch Surg. 1999;134:361–7. [PubMed: 10199307]
  8. Cohn RD, van Erp C, Habashi JP, Soleimani AA, Klein EC, Lisi MT, Gamradt M, ap Rhys CM, Holm TM, Loeys BL, Ramirez F, Judge DP, Ward CW, Dietz HC. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med. 2007;13:204–10. [PMC free article: PMC3138130] [PubMed: 17237794]
  9. David TE, Armstrong S, Ivanov J, Webb GD. Aortic valve sparing operations: an update. Ann Thorac Surg. 1999;67:1840–2. [PubMed: 10391321]
  10. Davies RR, Goldstein LJ, Coady MA, Tittle SL, Rizzo JA, Kopf GS, Elefteriades JA. Yearly rupture or dissection rates for thoracic aortic aneurysms: simple prediction based on size. Ann Thorac Surg. 2002;73:17–27. [PubMed: 11834007]
  11. De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996;62:417–26. [PubMed: 8723076]
  12. Disabella E, Grasso M, Marziliano N, Ansaldi S, Lucchelli C, Porcu E, Tagliani M, Pilotto A, Diegoli M, Lanzarini L, Malattia C, Pelliccia A, Ficcadenti A, Gabrielli O, Arbustini E. Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects. Eur J Hum Genet. 2006;14:34–8. [PubMed: 16251899]
  13. Francke U, Berg MA, Tynan K, Brenn T, Liu W, Aoyama T, Gasner C, Miller DC, Furthmayr H. A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection. Am J Hum Genet. 1995;56:1287–96. [PMC free article: PMC1801106] [PubMed: 7762551]
  14. Glancy DL, Wegmann M, Dhurandhar RW. Aortic dissection and patent ductus arteriosus in three generations. Am J Cardiol. 2001;87:813–5. [PubMed: 11249915]
  15. Gott VL, Greene PS, Alejo DE, Cameron DE, Naftel DC, Miller DC, Gillinov AM, Laschinger JC, Pyeritz RE. Replacement of the aortic root in patients with Marfan's syndrome. N Engl J Med. 1999;340:1307–13. [PubMed: 10219065]
  16. Gretarsdottir S, Baas AF, Thorleifsson G, Holm H, den Heijer M, de Vries JP, Kranendonk SE, Zeebregts CJ, van Sterkenburg SM, Geelkerken RH, van Rij AM, Williams MJ, Boll AP, Kostic JP, Jonasdottir A, Jonasdottir A, Walters GB, Masson G, Sulem P, Saemundsdottir J, Mouy M, Magnusson KP, Tromp G, Elmore JR, Sakalihasan N, Limet R, Defraigne JO, Ferrell RE, Ronkainen A, Ruigrok YM, Wijmenga C, Grobbee DE, Shah SH, Granger CB, Quyyumi AA, Vaccarino V, Patel RS, Zafari AM, Levey AI, Austin H, Girelli D, Pignatti PF, Olivieri O, Martinelli N, Malerba G, Trabetti E, Becker LC, Becker DM, Reilly MP, Rader DJ, Mueller T, Dieplinger B, Haltmayer M, Urbonavicius S, Lindblad B, Gottsäter A, Gaetani E, Pola R, Wells P, Rodger M, Forgie M, Langlois N, Corral J, Vicente V, Fontcuberta J, España F, Grarup N, Jørgensen T, Witte DR, Hansen T, Pedersen O, Aben KK, de Graaf J, Holewijn S, Folkersen L, Franco-Cereceda A, Eriksson P, Collier DA, Stefansson H, Steinthorsdottir V, Rafnar T, Valdimarsson EM, Magnadottir HB, Sveinbjornsdottir S, Olafsson I, Magnusson MK, Palmason R, Haraldsdottir V, Andersen K, Onundarson PT, Thorgeirsson G, Kiemeney LA, Powell JT, Carey DJ, Kuivaniemi H, Lindholt JS, Jones GT, Kong A, Blankensteijn JD, Matthiasson SE, Thorsteinsdottir U, Stefansson K. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nat Genet. 2010;42:692–7. [PubMed: 20622881]
  17. Guo D, Hasham S, Kuang SQ, Vaughan CJ, Boerwinkle E, Chen H, Abuelo D, Dietz HC, Basson CT, Shete SS, Milewicz DM. Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14. Circulation. 2001;103:2461–8. [PubMed: 11369686]
  18. Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, Bourgeois S, Estrera AL, Safi HJ, Sparks E, Amor D, Ades L, McConnell V, Willoughby CE, Abuelo D, Willing M, Lewis RA, Kim DH, Scherer S, Tung PP, Ahn C, Buja LM, Raman CS, Shete SS, Milewicz DM. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39:1488–93. [PubMed: 17994018]
  19. Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, Johnson RJ, Kim DH, Pannu H, Willing MC, Sparks E, Pyeritz RE, Singh MN, Dalman RL, Grotta JC, Marian AJ, Boerwinkle EA, Frazier LQ, LeMaire SA, Coselli JS, Estrera AL, Safi HJ, Veeraraghavan S, Muzny DM, Wheeler DA, Willerson JT, Yu RK, Shete SS, Scherer SE, Raman CS, Buja LM, Milewicz DM. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009;84:617–27. [PMC free article: PMC2680995] [PubMed: 19409525]
  20. Gupta PA, Wallis DD, Chin TO, Northrup H, Tran-Fadulu VT, Towbin JA, Milewicz DM. FBN2 mutation associated with manifestations of Marfan syndrome and congenital contractural arachnodactyly. J Med Genet. 2004;41:e56. [PMC free article: PMC1735765] [PubMed: 15121784]
  21. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312:117–21. [PMC free article: PMC1482474] [PubMed: 16601194]
  22. Hahn RT, Roman MJ, Mogtader AH, Devereux RB. Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves. J Am Coll Cardiol. 1992;19:283–8. [PubMed: 1732353]
  23. Helgadottir A, Thorleifsson G, Magnusson KP, Grétarsdottir S, Steinthorsdottir V, Manolescu A, Jones GT, Rinkel GJ, Blankensteijn JD, Ronkainen A, Jääskeläinen JE, Kyo Y, Lenk GM, Sakalihasan N, Kostulas K, Gottsäter A, Flex A, Stefansson H, Hansen T, Andersen G, Weinsheimer S, Borch-Johnsen K, Jorgensen T, Shah SH, Quyyumi AA, Granger CB, Reilly MP, Austin H, Levey AI, Vaccarino V, Palsdottir E, Walters GB, Jonsdottir T, Snorradottir S, Magnusdottir D, Gudmundsson G, Ferrell RE, Sveinbjornsdottir S, Hernesniemi J, Niemelä M, Limet R, Andersen K, Sigurdsson G, Benediktsson R, Verhoeven EL, Teijink JA, Grobbee DE, Rader DJ, Collier DA, Pedersen O, Pola R, Hillert J, Lindblad B, Valdimarsson EM, Magnadottir HB, Wijmenga C, Tromp G, Baas AF, Ruigrok YM, van Rij AM, Kuivaniemi H, Powell JT, Matthiasson SE, Gulcher JR, Thorgeirsson G, Kong A, Thorsteinsdottir U, Stefansson K. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008;40:217–24. [PubMed: 18176561]
  24. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM. American College of Cardiology Foundation; ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Catheter Cardiovasc Interv. 2010;76:E43–86. [PubMed: 20687249]
  25. Hoyert DL, Arias E, Smith BL, Murphy SL, Kochanek KD. Deaths: final data for 1999. Natl Vital Stat Rep. 2001;49(8):1–113. [PubMed: 11591077]
  26. Hutchinson S, Furger A, Halliday D, Judge DP, Jefferson A, Dietz HC, Firth H, Handford PA. Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: a potential modifier of phenotype? Hum Mol Genet. 2003;12:2269–76. [PubMed: 12915484]
  27. Inamoto S, Kwartler CS, Lafont AL, Liang YY, Fadulu VT, Duraisamy S, Willing M, Estrera A, Safi H, Hannibal MC, Carey J, Wiktorowicz J, Tan FK, Feng XH, Pannu H, Milewicz DM. TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections. Cardiovasc Res. 2010;88:520–9. [PMC free article: PMC2972687] [PubMed: 20628007]
  28. Jones KB, Myers L, Judge DP, Kirby PA, Dietz HC, Sponseller PD. Toward an understanding of dural ectasia: a light microscopy study in a murine model of Marfan syndrome. Spine. 2005;30(3):291–3. [PubMed: 15682009]
  29. Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest. 2004;114:172–81. [PMC free article: PMC449744] [PubMed: 15254584]
  30. Katzke S, Booms P, Tiecke F, Palz M, Pletschacher A, Türkmen S, Neumann LM, Pregla R, Leitner C, Schramm C, Lorenz P, Hagemeier C, Fuchs J, Skovby F, Rosenberg T, Robinson PN. TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat. 2002;20:197–208. [PubMed: 12203992]
  31. Khau Van Kien P, Mathieu F, Zhu L, Lalande A, Betard C, Lathrop M, Brunotte F, Wolf JE, Jeunemaitre X. Mapping of familial thoracic aortic aneurysm/dissection with patent ductus arteriosus to 16p12.2-p13.13. Circulation. 2005;112:200–6. [PubMed: 15998682]
  32. Khau Van Kien P, Wolf JE, Mathieu F, Zhu L, Salve N, Lalande A, Bonnet C, Lesca G, Plauchu H, Dellinger A, Nivelon-Chevallier A, Brunotte F, Jeunemaitre X. Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity. Eur J Hum Genet. 2004;12:173–80. [PubMed: 14722581]
  33. Ki CS, Jin DK, Chang SH, Kim JE, Kim JW, Park BK, Choi JH, Park IS, Yoo HW. Identification of a novel TGFBR2 gene mutation in a Korean patient with Loeys-Dietz aortic aneurysm syndrome; no mutation in TGFBR2 gene in 30 patients with classic Marfan's syndrome. Clin Genet. 2005;68:561–3. [PubMed: 16283890]
  34. Körkkö J, Kaitila I, Lönnqvist L, Peltonen L, Ala-Kokko L. Sensitivity of conformation sensitive gel electrophoresis in detecting mutations in Marfan syndrome and related conditions. J Med Genet. 2002;39:34–41. [PMC free article: PMC1734965] [PubMed: 11826022]
  35. Law C, Bunyan D, Castle B, Day L, Simpson I, Westwood G, Keeton B. Clinical features in a family with an R460H mutation in transforming growth factor beta receptor 2 gene. J Med Genet. 2006;43:908–16. [PMC free article: PMC2563201] [PubMed: 16885183]
  36. LeMaire SA, Pannu H, Tran-Fadulu V, Carter SA, Coselli JS, Milewicz DM. Severe aortic and arterial aneurysms associated with a TGFBR2 mutation. Nat Clin Pract Cardiovasc Med. 2007;4:167–71. [PMC free article: PMC2561071] [PubMed: 17330129]
  37. Lewis RA, Merin LM. Iris flocculi and familial aortic dissection. Arch Ophthalmol. 1995;113:1330–1. [PubMed: 7575269]
  38. Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275–81. [PubMed: 15731757]
  39. Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788–98. [PubMed: 16928994]
  40. Loscalzo ML, Goh DL, Loeys B, Kent KC, Spevak PJ, Dietz HC. Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance. Am J Med Genet A. 2007;143A:1960–7. [PubMed: 17676603]
  41. Mátyás G, Arnold E, Carrel T, Baumgartner D, Boileau C, Berger W, Steinmann B. Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Hum Mutat. 2006;27:760–9. [PubMed: 16791849]
  42. Milewicz DM, Chen H, Park ES, Petty EM, Zaghi H, Shashidhar G, Willing M, Patel V. Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections. Am J Cardiol. 1998;82:474–9. [PubMed: 9723636]
  43. Milewicz DM, Michael K, Fisher N, Coselli JS, Markello T, Biddinger A. Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation. 1996;94:2708–11. [PubMed: 8941093]
  44. Milewicz DM, Østergaard JR, Ala-Kokko LM, Khan N, Grange DK, Mendoza-Londono R, Bradley TJ, Olney AH, Adès L, Maher JF, Guo D, Buja LM, Kim D, Hyland JC, Regalado ES. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A. 2010;152A:2437–43. [PMC free article: PMC3573757] [PubMed: 20734336]
  45. Mizuguchi T, Collod-Beroud G, Akiyama T, Abifadel M, Harada N, Morisaki T, Allard D, Varret M, Claustres M, Morisaki H, Ihara M, Kinoshita A, Yoshiura K, Junien C, Kajii T, Jondeau G, Ohta T, Kishino T, Furukawa Y, Nakamura Y, Niikawa N, Boileau C, Matsumoto N. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet. 2004;36:855–60. [PMC free article: PMC2230615] [PubMed: 15235604]
  46. Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407–11. [PubMed: 12598898]
  47. Ng CM, Cheng A, Myers LA, Martinez-Murillo F, Jie C, Bedja D, Gabrielson KL, Hausladen JM, Mecham RP, Judge DP, Dietz HC. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest. 2004;114:1586–92. [PMC free article: PMC529498] [PubMed: 15546004]
  48. Pannu H, Fadulu VT, Chang J, Lafont A, Hasham SN, Sparks E, Giampietro PF, Zaleski C, Estrera AL, Safi HJ, Shete S, Willing MC, Raman CS, Milewicz DM. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation. 2005;112:513–20. [PubMed: 16027248]
  49. Pannu H, Tran-Fadulu V, Papke CL, Scherer S, Liu Y, Presley C, Guo D, Estrera AL, Safi HJ, Brasier AR, Vick GW, Marian AJ, Raman CS, Buja LM, Milewicz DM. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16:2453–62. [PMC free article: PMC2905218] [PubMed: 17666408]
  50. Pape LA, Tsai TT, Isselbacher EM, Oh JK. Aortic diameter >or = 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2007;116:1120–7. [PubMed: 17709637]
  51. Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, Clarke L, Bernier F, Santos-Cortez RL, Leal SM, Bertoli-Avella AM, Shendure J, Rieder MJ, Nickerson DA. NHLBI GO Exome Sequencing Project, Milewicz DM. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res. 2011;109:680–6. [PMC free article: PMC4115811] [PubMed: 21778426]
  52. Roman MJ, Rosen SE, Kramer-Fox R, Devereux RB. Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome. J Am Coll Cardiol. 1993;22:1470–6. [PubMed: 8227807]
  53. Ross S, Hill CS. How the Smads regulate transcription. Int J Biochem Cell Biol. 2008;40:383–408. [PubMed: 18061509]
  54. Rossiter JP, Repke JT, Morales AJ, Murphy EA, Pyeritz RE. A prospective longitudinal evaluation of pregnancy in the Marfan syndrome. Am J Obstet Gynecol. 1995;173:1599–606. [PubMed: 7503207]
  55. Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700. [PubMed: 12809600]
  56. Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta- adrenergic blockade in Marfan's syndrome. N Engl J Med. 1994;330:1335–41. [PubMed: 8152445]
  57. Singh KK, Rommel K, Mishra A, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat. 2006;27:770–7. [PubMed: 16799921]
  58. Stheneur C, Collod-Béroud G, Faivre L, Buyck JF, Gouya L, Le Parc JM, Moura B, Muti C, Grandchamp B, Sultan G, Claustres M, Aegerter P, Chevallier B, Jondeau G, Boileau C. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009;17:1121–8. [PMC free article: PMC2986588] [PubMed: 19293843]
  59. Tang PC, Coady MA, Lovoulos C, Dardik A, Aslan M, Elefteriades JA, Tellides G. Hyperplastic cellular remodeling of the media in ascending thoracic aortic aneurysms. Circulation. 2005;112:1098–105. [PubMed: 16116068]
  60. Tilson MD, Seashore MR. Fifty families with abdominal aortic aneurysms in two or more first-order relatives. Am J Surg. 1984;147:551–3. [PubMed: 6538765]
  61. Tran-Fadulu V, Pannu H, Kim DH, Vick GW, Lonsford CM, Lafont AL, Boccalandro C, Smart S, Peterson KL, Hain JZ, Willing MC, Coselli JS, LeMaire SA, Ahn C, Byers PH, Milewicz DM. Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J Med Genet. 2009;46:607–13. [PubMed: 19542084]
  62. van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collée M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IM, Micha D, Timmermans J, Hilhorst-Hofstee Y, Bierma-Zeinstra SM, Willems PJ, Kros JM, Oei EH, Oostra BA, Wessels MW, Bertoli-Avella AM. Nat Genet. 2011;43(2):121–6. [PubMed: 21217753]
  63. Vaughan CJ, Casey M, He J, Veugelers M, Henderson K, Guo D, Campagna R, Roman MJ, Milewicz DM, Devereux RB, Basson CT. Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder. Circulation. 2001;103:2469–75. [PubMed: 11369687]
  64. Vollbrandt T, Tiedemann K, El-Hallous E, Lin G, Brinckmann J, John H, Bätge B, Notbohm H, Reinhardt DP. Consequences of cysteine mutations in calcium-binding epidermal growth factor modules of fibrillin-1. J Biol Chem. 2004;279:32924–31. [PubMed: 15161917]
  65. Wang L, Guo DC, Cao J, Gong L, Kamm KE, Regalado E, Li L, Shete S, He WQ, Zhu MS, Offermanns S, Gilchrist D, Elefteriades J, Stull JT, Milewicz DM. Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet. 2010;87:701–7. [PMC free article: PMC2978973] [PubMed: 21055718]
  66. Watterson DM, Schavocky JP, Guo L, Weiss C, Chlenski A, Shirinsky VP, Van Eldik LJ, Haiech J. Analysis of the kinase-related protein gene found at human chromosome 3q21 in a multi-gene cluster: organization, expression, alternative splicing, and polymorphic marker. J Cell Biochem. 1999;75:481–91. [PubMed: 10536370]
  67. Zhu L, Vranckx R, Van Kien PK, Lalande A, Boisset N, Mathieu F, Wegman M, Glancy L, Gasc JM, Brunotte F, Bruneval P, Wolf JE, Michel JB, Jeunemaitre X. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006;38:343–9. [PubMed: 16444274]

Chapter Notes

Author History

Dianna M Milewicz, MD, PhD (2003-present)
Ellen Regalado, MS, CGC (2011-present)
Van Tran-Fadulu, MS, CGC; University of Texas Medical School (2003-2011)

Revision History

  • 12 January 2012 (cd) Revision: MYLK and SMAD3 mutations found to cause TAAD (testing available); multi-gene testing panels now listed in GeneTests™ Laboratory Directory
  • 11 January 2011 (me) Comprehensive update posted live
  • 13 January 2009 (cd) Revision: clinical testing available for mutations in ACTA2 and MYH1
  • 6 January 2009 (cd) Revision: ACTA2 mutations responsible for 14% of inherited TAAD; TGFBR1 mutations also responsible for some cases of inherited TAAD
  • 10 May 2006 (me) Comprehensive update posted to live Web site
  • 28 April 2005 (me) Comprehensive update posted to live Web site
  • 13 February 2003 (me) Review posted to live Web site
  • 11 July 2002 (dm) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1120PMID: 20301299
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...