FBN1 Genetic Analysis, Known Mutation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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 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 and 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.
Genetic testing of individuals at risk for a known FBN1 mutation
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test is for individuals who are at risk for a FBN1 mutation that has been previously identified in the family. If the familial mutation is not known, the familial proband should be screened for an FBN1 mutation using 1 of the following:
-FBN1 / FBN1 Full Gene Sequence
-FBNN / FBN1, Partial Gene Sequence, Neonatal Marfan Syndrome
Any error in the diagnosis or pedigree provided to us, including false-paternity, could lead to erroneous interpretation of results.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Faivre L, Collod-Beroud G, Loeys BL, et al: Effect of mutation type and location on clinical outcome of 1013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007 Sept;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 2005May;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 Feb;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