Marfan Syndrome, Type 2 - TGFBR1 Gene

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Gene Symbol: TGFBR1    
    
Chromosomal Locus: 9q22.33       
                                               
Protein: Transforming growth factor, beta receptor I   
               
Related Syndromes: Marfan syndrome, MASS syndrome, Shprintzen-Goldberg syndrome
 
Pseudonyms: Loeys-Dietz syndrome (LDS), TGF-beta receptor type-1, fibrillin 1, fibrillin-15, MASS, WMS
 
TURNAROUND TIME:     4 weeks
 
TESTING METHODOLOGY: Polymerase chain reaction (PCR) followed by bidirectional sequencing of the coding regions of the gene and the intron / exon borders.
 
SPECIMEN REQUIREMENTS:
  • Collect:  Prefer two 5ml whole blood EDTA (lavender top) tube. 
  • Min. Collection: 0.7 ml whole blood EDTA.
  • Transport: Blood EDTA at Room Temp shipped next day air (No Saturday delivery; store specimen refrigerated and ship Monday).
  • Stability: Ambient: up to 7 days; Refrigerated: 2 weeks. Frozen: unacceptable
  • Unacceptable Conditions: Serum. Frozen or severely hemolyzed blood. Clotted blood.
  • Prenatal testing:  Direct: 5ml direct unspun amniotic fluid or 15mg CVS tissue with a backup flask growing. Culture: confluent T25 flask.  Maternal blood sample is required for maternal cell contamination studies.     
A Molecular Genetics Laboratory Test Requisition must accompany the specimen. Contact the Molecular Laboratory at 918-502-1721 to obtain further information.
 
Note: Counseling and informed consent are recommended for genetic testing. A consent form is available as a resource but not required.
 
INTERPRETATIVE DATA:
 
Incidence: 1 in 5,000 (Marfan - like symptoms)
 
Inheritance: Autosomal dominant.
 
Disease Characteristics: Marfan syndrome is a connective tissue disorder with striking pleiotropism and clinical variability. Cardiac features are dilatation of the aortic root, aneurysm of the aorta and aortic dissectionThe cardiac symptoms often lead to premature death. Skeletal features are increased height, disproportionately long limbs, chest deformity, joint laxity, scoliosis and a narrow, highly arched palate with crowding of the teeth. Ocular features include myopia and ectopia lentis.
 
Classical Loeys-Dietz syndrome (LDS) is also an autosomal dominant aortic aneurysm syndrome. LDS is characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. The natural history of both conditions is characterized by aggressive arterial aneurysms and a high rate of pregnancy-related complications. The overlap of symptoms for these two conditions requires that a full analysis of Marfan syndrome must be extended to include reflexive analysis of the TGFBR1 and TGFBR2 genes.
 
Molecular Genetic Mechanism:  A variety of missense and nonsense mutations have been described throughout the gene. The mutations interfere with the normal serine-threonine kinase activity of the gene and block normal signal transduction by protein phosphorylation.
 
 
Clinical Sensitivity: 10 -15% of individuals with a clinical diagnosis of Marfan Syndrome will have a mutation in the coding regions of TGFBR1.
 
Analytical Sensitivity: 99%.
 
Test Limitations: Deletions of entire exons or the entire gene are not detected.  Mutations that are not in the coding sequence of the TGFBR1 gene will not be detected. Rare diagnostic errors can occur due to primer or probe site mutations or rare polymorphisms.
 
INDICATIONS FOR USE:
  • To confirm a clinical diagnosis and clarify therapeutic options.
  • To evaluate the inheritance risk of aortic dissection and death in a family with known history.
  • Symptomatic patients that did not have mutations in the FBN1 gene.
  • Prenatal diagnosis for Individuals at risk due to family history
ADDITIONAL RESOURCES:
OMIM - Loeys-Dietz Syndrome: http://omim.org/entry/609192
OMIM - Marfan syndrome: www.omim.org/entry/154700
OMIM Shprintzen-Goldberg Craniosynostosis: www.omim.org/entry/182212
OMIM Mass syndrome: www.omim.org/entry/604308