Step 1: LOEYS-DIETZ Syndrome Phenotype - TGBR1 and TGFBR2 gDNA Sequencing
Mutations in the TGFB receptor genes give rise to clinical phenotypes that overlap with those seen in the Marfan syndrome, including aortic aneurysm, but can include hypertelorism (wide spaced eyes), generalized arterial tortuosity, craniosynostosis, cleft palate, bifid uvula, congenital heart disease, and mental retardation. In some families only aortic root enlargement with risk of early dissection has been recognized while in others the phenotype is more complex. Involvement of vascular vessels other than the aorta are reported as well.
The TGFB receptors mediate the signaling of the TGFb cytokines and of members of the same large cytokine family. Mutations in the receptor genes have been found to give rise to clinical phenotypes that overlap with those seen in the Marfan syndrome, including aortic aneurysm, but can include hypertelorism (wide spaced eyes), generalized arterial tortuosity, craniosynostosis, cleft palate, bifid uvula, congenital heart disease, and mental retardation (Mizuguchi et al. 2004; Loeys et al. 2005; Loeys et al. 2006; Stheneur et al. 2008). This spectrum represents the sum of findings in almost ninety families and it is important to emphasize that in a given family only a few of these findings may be present. In some families only aortic root enlargement with risk of early dissection has been recognized while in others the phenotype may be more complex. It is very likely that the clinical presentation depends on the nature and location of the mutation in the gene and the effect that the mutation has on the function of the receptor. The genotype/phenotype correlation has not yet been established and will likely emerge as more mutations are identified.
2. Familial Aneurysm (Indistinct Phenotype) - gDNA sequencing of five genes: TGFBR1, TGFBR2, COL3A1, SMAD3 and ACTA2
The Collagen Diagnostic Lab offers testing of FIVE genes for four inherited aneurysmal disorders as a single VASCULAR PANEL as well as testing for individual genes. The decision about which test to choose for your patient is determined by clinical presentation, medical history and family history. If your patient has features that overlap the described disorders, the VASCULAR PANEL yields faster results at a reduced cost per test.
References:
Loeys BL et al. (2005) A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37:275-81
Loeys BL et al.(2006) Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355:788-98
Mizuguchi T et al. (2004) Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36:855-60
Stheneur C et al. (2008) 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 Mutation in Brief #1031,29:E284-E295