Background
Aortic aneurysms are relatively common, accounting for about 15,000 deaths annually in the US. Approximately 20% result from a genetic predisposition. Familial Thoracic Aortic Aneurysms and Aortic Dissections (TAAD, OMIM# 607086, 608967) is characterized by cardiovascular manifestations, which include dilation of the aorta and aneurysms and dissections of the thoracic aorta involving either the ascending or descending aorta. The dilation of the aorta is usually at either the level of the ascending aorta and/or the sinuses of Valsalva. Individuals who are affected usually have progressive enlargement of the ascending aorta which leads to either aortic dissection involving the ascending aorta or consequent tear and rupture (Milewicz 2006). The cardiovascular manifestations are usually the only clinical features; however inguinal hernias, iris flocculi and livedo reticularis have been reported in some families (Guo 2007, Milewicz 2006). Individuals are diagnosed with TAAD based on cardiovascular manifestations, a positive family history, and the absence of Marfan syndrome, Loeys-Dietz syndrome or other connective tissue abnormalities (Milewicz 2006). The age of onset and rate of progression of aortic dilation are highly variable even within families. TAAD has an autosomal dominant inheritance pattern. Of individuals with TAAD approximately 14% have mutations in
ACTA2 and 5-9% have mutations in
TGFβR2. In addition,
TGFβR1and
FBN1 mutations have also been reported in individuals with TAAD. Other genes and loci have also been associated with TAAD (
MYH11,
TAAD1 and
FAA1).
In addition to confirming the diagnosis of TAAD in patients with clinically evident disease, genetic testing allows for early identification and diagnosis of individuals at greatest risk prior to the expression of cardiac manifestations. If a mutation is identified in an individual who is not expressing symptoms, regular and serial outpatient follow up is indicated. Referral to a specialist with specific expertise in the management of TAAD is highly recommended for patients with established disease as well as their family members. If clinically unaffected members of a family with an identified mutation for TAAD are found not to carry that mutation (genotype negative), they can be definitively diagnosed as unaffected with TAAD and reassured that neither they nor their offspring will be at higher risk compared to the general population to develop thoracic aortic aneurysms or dissections. The need for serial follow up is also obviated.
Synonyms
- AAT1
- FAA1
- ANNULOAORTIC ECTASIA
- AORTIC DISSECTION, FAMILIAL
- AORTIC ANEURYSM, FAMILIAL THORACIC
- ANEURYSM, THORACIC AORTIC
- ERDHEIM CYSTIC MEDIAL NECROSIS OF AORTA
| Gene |
Name |
OMIM# |
Locus |
| ACTA2 |
Smooth Muscle α-actin |
102620 |
10q22-q24 |
| TGFβR2 |
Transforming Growth Factor-Beta Receptor, Type II |
190182 |
3p22 |
| TGFβR1 |
Transforming Growth Factor-Beta Receptor, Type I |
190181 |
9q33-34 |
| FBN1 |
Fibrillin 1 |
134797 |
15q21.1 |
- Other diseases caused by mutations in TGFβR2
- Loeys Dietz aortic aneurysm (OMIM#609192)
- MARFAN SYNDROME, TYPE II; MFS2 (OMIM#154705)
- Other diseases caused by mutations in TGFβR1
- Loeys Dietz aortic aneurysm (OMIM#609192)
- Familial thoracic aortic aneurysms, Type III (OMIM# 608967)
- Furlong syndrome (OMIM#610168)
- Other diseases caused by mutations in FBN1
- Shprintzen-Goldberg Craniosynostosis Syndrome (OMIM# 182212)
- Weill-Marchesani Syndrome (OMIM# 608328)
- Mass Syndrome (OMIM# 604328)
- Isolated Ectopia Lentis (OMIM# 129600)
- Inherited form of aortic aneurysms
Epidemiology
- Aortic aneurysms account for ~15,000 deaths annually (13th major cause of death in the US) with ~20% resulting from a genetic predisposition.
- Males and females are affected in equal frequency.
- No known racial predilection.
Inheritance Pattern: Autosomal dominant
- The presence of a pathogenic mutation in one copy of the ACTA2, TGFβR2, TGFβR1 or FBN1 is sufficient to cause TAAD.
- Children of an affected individual with an identified pathogenic mutation have a 50% (or 1 in 2) risk of inheriting the same mutation.
- Reduced penetrance and variable expression, even within a family, have been reported.
- De novo mutations in TGFβR2 have been reported (Mizuguchi D 2007, Matyas G 2006)
- Somatic and germline mosaicism have been reported for FBN1.
Test Indications
- Patients with:
- Dilation of the aorta at the level or either the ascending aorta or the sinuses of Valsalva.
- Aneurysms and dissections of the thoracic aorta involving either the ascending or descending aorta.
- Positive family history
- Exclusion of Marfan syndrome, Loeys-Dietz syndrome, and other connective tissue abnormalities.
- Parents, siblings, and possibly children of a patient known to carry a mutation in ACTA2, TGFβR2, TGFβR1 or FBN1.
- Prenatal testing when a parent is diagnosed with TAAD and has an identified ACTA2, TGFβR2, TGFβR1 or FBN1 mutation.
Test Outcome
- The detection of a pathogenic mutation in one copy of the ACTA2, TGFβR2, TGFβR1 or FBN1 gene is considered a positive test result. A positive test result can confirm a suspected diagnosis of TAAD. If a familial mutation is known, this result confirms the presence of the mutation in a family member.
- Mutations in TGFβR2, TGFβR1 or FBN1 can also be associated with Marfan syndrome or Loeys-Dietz syndrome. Therefore, individuals with a positive test results should be evaluated for additional features associated with these syndromes.
- A negative ACTA2, TGFβR2, TGFβR1 or FBN1 test result does not rule out TAAD. A mutation may be detected in approximately 19% of individuals with TAAD. Other genes and genetic loci have been associated with TAAD.
- Referral to a genetics center and specialists with expertise in the management of TAAD is highly recommended.
Turn-Around-Times
- ACTA2 Gene Sequencing: 3 weeks
- TGFβR2 Gene Sequencing: 3 weeks
- TGFβR1 Gene Sequencing: 3 weeks
- FBN1 Gene Sequencing: 6 weeks
Methodology
Bi-directional sequence analysis is performed on 8 exons and splice sites in
ACTA2, 7 exons and splice sites of
TGFβR2, 9 exons and splice sites of
TGFβR1 or 65 exons and splice sites in
FBN1. This test does not detect additional mutations in non-coding regions that could affect gene expression or deletions encompassing a large portion of the genes.
Analytical Sensitivity
This assay has greater than 99.9% accuracy to detect mutations in the sequence analyzed.
Clinical Sensitivity
The overall detection rate of pathogenic mutations in individuals with a clinical diagnosis of TAAD is approximately 14% in
ACTA2 and 5% in
TGFβR2 (Guo 2007; Matyas 2006). The detection rates for pathogenic mutations in
FBN1 and
TGFβR2 are unknown at this time.
Cost and CPT codes:
ACTA2 Gene Sequencing
- Cost: $599
- CPT codes: 83891(1), 83894(1), 83898(8), 83904(8), 83909(1), 83912(1)
TGFβR2 Gene Sequencing
- Cost: $599
- CPT codes: 83891(1), 83894(1), 83898(9), 83904(9), 83909(1), 83912(1)
TGFβR1 Gene Sequencing
- Cost: $599
- CPT codes: 83891(1), 83894(1), 83898(5), 83904(5), 83909(1), 83912(1)
FBN1 Gene Sequencing
- Cost: $1599
- CPT codes: 83891(1), 83894(1), 83898(9), 83904(9), 83909(1), 83912(1)
Testing for Known Familial Mutation:
- Cost: $250
- CPT codes: 83891(1), 83894(1), 83898(1), 83904(1), 83909(1), 83912(1)
References:
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, Willings M, Lewis RA, Kim DH, Scherer S, Tung PP, Ahn C, Buja M, Raman CS, Shete SS, Milewicz D. (2007) Mutations in smooth muschle α-actin (
ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Gen 36(12):1448-93
M??ty??s G, Arnold E, Carrel T, Baumgartner D, Boileau C, Berger W, Steinmann B. (2006) Identification and in silico analyses of novel
TGFβR2 and
TGFβR2 mutations in Marfan syndrome-related disorders. Hum Mutat. 27(8):760-9.
Milewicz DM, Tran-Fadulu V (2006) Thoracic aortic aneurysms and aortic dissections. In GeneReviews at GeneTests http://www.genetests.org.
Mizuguchi T, Matsumoto N. (2007) Recent progress in genetics of Marfan syndrome and Marfan-associated disorders. J Hum Genet 52:1-12
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