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Fibrillin-1 is a 320-kD cysteine-rich glycoprotein found in the extracellular matrix. Monomers of fibrillin-1 associate to form microfibrils, which provide mechanical stability and elastic properties to connective tissues. Fibrillin-1 is encoded by the FBN1 gene, which contains 65 exons and is located at chromosome 15q21.
FBN1 mutations are most commonly associated with Marfan syndrome (MFS), an autosomal dominant connective tissue disorder involving the ocular, skeletal, and cardiovascular systems. Ocular MFS manifestations most commonly include myopia and lens displacement. Skeletal manifestations can include arachnodactyly (abnormally long and slender fingers and toes), dolichostenomelia (long limbs), pectus (chest wall) deformity, and scoliosis. Cardiovascular manifestations, which are the major cause of early morbidity and mortality in MFS, include aortic dilation and aortic aneurysm and dissection, as well as mitral valve and tricuspid valve prolapse. There is significant inter- and intrafamilial variability in MFS phenotype.
FBN1 mutations have also been reported in several other rare phenotypes with variable overlap with classic MFS. These conditions include neonatal MFS, autosomal dominant ectopia lentis (displacement of the lens of the eye), familial thoracic aortic aneurysm and dissection, isolated skeletal features of MFS, MASS phenotype (mitral valve prolapse, aortic diameter increased, stretch marks, skeletal features of MFS), Shprintzen-Goldberg syndrome (Marfanoid-craniosynostosis; premature ossification and closure of sutures of the skull), and autosomal dominant Weill-Marchesani syndrome (short stature, short fingers, ectopia lentis).
Hundreds of mutations have been identified in FBN1, many of them unique to individual families. There is a wide range of variability, including intrafamilial variability, in expressivity among FBN1 mutations. Approximately two thirds of FBN1 mutations are missense mutations, with the majority of these being cysteine substitutions. Approximately 25% to 33% of FBN1 mutations are de novo mutations, in which an individual has no family history of disease. FBN1 mutations have been shown to occur across the gene with very few genotype-phenotype correlations, with the exception of the association of neonatal MFS and mutations in exons 24 through 32.
Genetic testing for FBN1 mutations allows for the confirmation of a suspected genetic disease. Confirmation of MFS or other FBN1-associated genetic diseases allows for proper treatment and management of the disease and preconception, prenatal, and family counseling.
Aiding in the diagnosis of FBN1-associated Marfan syndrome, neonatal Marfan syndrome, autosomal dominant ectopia lentis, isolated ascending aortic aneurysm and dissection, isolated skeletal features of Marfan syndrome, MASS phenotype, Shprintzen-Goldberg syndrome, and autosomal dominant Weill-Marchesani syndrome
An interpretive report will be provided.
Blood samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient’s genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.
Related FBN1 genetic tests are:
-FBNN / FBN1, Partial Gene Sequence, Neonatal Marfan Syndrome provides sequencing of exons 24 through 33
-FBKM / FBN1 Genetic Analysis, Known Mutation used to test for a specific familial mutation
Absence of a mutation does not preclude the diagnosis of Marfan syndrome unless a specific mutation has already been identified in an affected family member.
This method will not detect mutations that occur in the introns (except in the splicing regions) and regulatory regions of the gene and large rearrangement-type mutations.
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.
1. Faivre L, Collod-Beroud G, Loeys BL, et al: Effect of mutation type and location on clinical outcome of 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007 Sep;81(3):454-466
2. Tjeldhorn L, Rand-Hendriksen S, Gervin K, et al: Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test 2006;10(4):258-264
3. Boileau C, Jondeau G, Mizuguchi T, Matsumoto N: Molecular genetics of Marfan syndrome. Curr Opin Cardiol 2005 May;20(3):194-200
4. Sood S, Eldadah ZA, Krause WL, et al: Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nat Genet 1996;12(2):209-211
5. Faivre L, Gorlin RJ, Wirtz MK, et al: In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet 2003 Jan;40(1):34-36