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TGF1
89459
TGFBR1, Full Gene Sequence
Clinical Information: Mutations in the TGFBR1 gene have been implicated in a range of
autosomal dominant conditions with a considerable degree of phenotypic overlap. The genetic disease
most commonly associated with TGFBR1 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 can also be caused
by mutations in the TGFBR2 gene. LDS is divided into LDS type I and LDS type II based on
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 TGFBR1 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 the TGFBR1 gene. Some individuals with mutations in
TGFBR1 present with features similar to those seen in vascular type Ehlers-Danlos syndrome (EDS
type IV), such as visceral rupture, easy bruising, wide and atrophic scars, joint laxity, translucent skin,
velvety skin, or both. In addition, familial thoracic aortic aneurysm and dissection (FTAAD), which
involves cardiovascular manifestations only, has been associated with mutations in TGFBR1. Mutations
in TGFBR1 may also be observed in Shprintzen Goldberg syndrome (SGS), which is characterized by
craniosynostosis, distinctive craniofacial features, skeletal changes, neurologic abnormalities, mental
retardation, and brain anomalies among other features. The TGFBR1 gene, which contains 9 exons and
is located on chromosome 9q22, encodes the transforming growth factor beta receptor I (TGF beta R-I).
TGF beta R-I is a 53 kilodalton 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 TGF beta to transforming growth factor beta receptor II (TGF beta
R-II), which then recruits and phosphorylates TGF beta R-I, propagating the signal to downstream
transcription factors. Few genotype-phenotype correlations exist for TGFBR1 mutations; indeed,
identical mutations have been reported to cause Marfan-like syndrome in some individuals, LDS in
others, and FTAAD in others. Approximately 25% of individuals with LDS have an affected parent;
while 75% have a de novo mutation (de novo rate for related phenotypes is not reported). TGFBR1
mutations can manifest with a range of phenotypes and variable ages of onset both between families and
amongst affected members of the same family. Thus, TGFBR1-related disorders can be diagnostically
challenging. Genetic testing for TGFBR1 mutations allows for the confirmation of a suspected genetic
disease. Confirmation of LDS or other TGFBR1-associated genetic diseases allows for proper treatment
and management of the disease. Additionally, mutation confirmation can allow for
preconception/prenatal and family counseling.
Useful For: Aiding in the diagnosis of TGFBR1-associated Loeys-Dietz syndrome, Marfan or
Marfan-like syndrome, familial thoracic aortic aneurysm and dissection syndrome, and
Shprintzen-Goldberg syndrome
Interpretation: An interpretive report will be provided.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Loeys B, Chen J, Neptune E, et al: A syndrome of altered cardiovascular,
craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.
Nat Genet 2005;37(3):275-281 2. Akutsu K, Morisaki H, Takeshita S, et al: Phenotypic heterogeneity of
Marfan-like connective tissue disorders associated with mutations in the transforming growth
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