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Mutations in the TGFBR2 gene have been implicated in a range of autosomal dominant conditions with considerable phenotypic overlap. The genetic disease most commonly associated with TGFBR2 mutations is Loeys-Dietz syndrome (LDS), which is characterized by cerebral, thoracic, and abdominal arterial aneurysms and/or dissections, as well as skeletal anomalies (chest abnormalities, scoliosis, joint laxity, arachnodactyly).
LDS is divided into LDS type I and LDS type II based on the phenotype, then further categorized depending on the causative gene. Both LDS type I and II involve the cardiovascular and skeletal manifestations mentioned above. In addition, LDS type I involves craniofacial manifestations including hypertelorism, bifid uvula/cleft palate, and craniosynostosis. LDS type I caused by a TGFBR1 mutation is known as LDS1A, whereas LDS type I caused by a TGFBR2 mutation, is known as LDS1B. LDS type II has cutaneous manifestations including velvety and translucent skin, easy bruising, widened and atrophic scars, and uterine rupture. LDS type II caused by a TGFBR1 mutation is known as LDS2A, whereas LDS type II caused by a TGFBR2 mutation is known as LDS2B. Identical mutations can lead to LDS type I or type II, supporting the belief that both types are part of a clinical continuum.
Mutations in the TGFBR2 gene have also been identified in conditions with phenotypic overlap with LDS. Marfan syndrome (MFS) is a systemic connective tissue disorder involving the ocular, skeletal, and cardiovascular systems. MFS is most often associated with mutations in the FBN1 gene; however some individuals who meet, or nearly meet, the clinical diagnostic criteria for MFS have been shown to have mutations in TGFBR2. Familial thoracic aortic aneurysm and dissection (TAAD), which involves cardiovascular manifestations only, has also been associated with mutations in TGFBR2. Shprintzen-Goldberg syndrome, a rare disorder characterized by marfanoid habitus, cardiovascular anomalies, mental retardation, and craniosynostosis, has been associated with a TGFBR2 mutation. TGFBR2 mutations have also been identified in individuals who phenotypically presented with vascular type Ehlers-Danlos syndrome (EDS), but tested negative for COL3A1 mutations (the gene typically associated with vascular EDS).
Transforming growth factor-beta receptor II (TGFBR-II) is a 70 to 80 kDa protein that belongs to the serine-threonine kinase family of cell surface receptors. This group of receptors regulates a variety of cellular processes including proliferation, differentiation, cell cycle arrest, apoptosis, and formation of the extracellular matrix. Receptor activation occurs upon binding of transforming growth factor-beta (TGFB) to TGFBR-II, which then recruits and phosphorylates TGFBR-I, propagating the signal to downstream transcription factors. TGFBR-II is encoded by the TGFBR2 gene, which contains 7 exons plus 2 variant exons and is located on chromosome 3p22.
Excluding TGFBR2 mutations reported in malignancies, more than 50 pathogenic TGFBR2 mutations have been associated with the syndromic features described above. The majority of these are missense mutations, although splice site and nonsense mutations have also been reported. The great majority of pathogenic mutations are located in the intracellular serine/threonine kinase domains. Few genotype-phenotype correlations exist for TGFBR2 mutations; indeed, identical mutations have been reported to cause MFS in some individuals and LDS in others. Approximately 25% of individuals with LDS have an affected parent, while 75% have a de novo mutation.
TGFBR2 mutations can manifest with a range of phenotypes and variable ages of onset both between families and among affected members of the same family. Thus, TGFBR2-related disorders can be diagnostically challenging. Genetic testing for TGFBR2 mutations allows for the confirmation of a suspected genetic disease. Confirmation of LDS or other TGFBR2-associated genetic diseases allows for proper treatment and management of the disease, and preconception/prenatal and family counseling. For example, in LDS, aortic dissection has been observed at aortic dimensions that do not confer risk in MFS caused by FBN1 mutations. Therefore, a more aggressive treatment strategy or earlier surgical intervention might be considered if an individual were found to have a TGFBR2 mutation rather than an FBN1 mutation.
Aiding in the diagnosis of TGFBR2-associated Loeys-Dietz syndrome, Marfan or Marfan-like syndrome, familial thoracic aortic aneurysm and dissection syndrome, and Shprintzen-Goldberg syndrome
An interpretive report will be provided.
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
Absence of a mutation does not preclude the diagnosis of Loeys-Dietz syndrome or another TGFBR2-related disorder unless a specific mutation has already been identified in an affected family member. To test family members, see TGFK2 / TGFBR2 Gene, Known Mutation.
This method will not detect mutations that occur in the introns (except in the splicing regions) and regulatory regions of the gene or large genomic rearrangement-type mutations.
Rare, undocumented polymorphisms may be present, which could lead to false-negative or false-positive results.
Sometimes a genetic alteration of unknown significance may be identified. In this case, testing of appropriate family members may be useful to determine pathogenicity of the alteration.
An interpretive report will be provided.
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2. Loeys B, Schwarze U, Holm T, et al: Aneurysm syndromes caused by mutations in the TGF-B receptor. N Engl J Med 2006;355(8):788-798
3. Akutsu K, Morisaki H, Takeshita S, et al: Phenotypic heterogeneity of Marfan-like connective tissue disorders associated with mutations in the transforming growth factor-beta receptor genes. Circ J 2007;71(8):1305-1309
4. Singh KK, Rommel K, Mishra A, et al: TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat 2006;27(8):770-777
5. Stheneur C, Collod-Beroud G, Faivre L, et al: Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. Hum Mutat 2008 Nov;29(11):E284-295