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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 phenotype.
Neonatal MFS is characterized by a more severe and rapidly progressing phenotype compared with classic MFS. Features can include congenital contractures, dilated cardiomyopathy, congestive heart failure, pulmonary emphysema, and mitral or tricuspid valve regurgitation in the newborn period. The majority of mutations associated with neonatal MFS occur in exons 24 through 32.
FBN1 mutations have also been reported in several other rare phenotypes with variable overlap with classic MFS. These conditions include 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.
Genetic testing for FBN1 mutations allows for the confirmation of a suspected genetic disease. Confirmation of neonatal 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 neonatal Marfan syndrome
An interpretive report will be provided.
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
Related FBN1 genetic tests available are:
-FBN1 / FBN1, Full Gene Sequence
-Testing for a specific familial mutation FBKM / FBN1 Genetic Analysis, Known Mutation
Absence of a mutation does not preclude the diagnosis of neonatal MFS. Some individuals who present with severe disease may not have an identifiable mutation in this region.
Presence of a mutation is not specifically diagnostic for neonatal MFS. Individuals with a mutation in this region may have classic MFS or a variant of MFS. Information pertaining to individual genotype should be assessed in the context of phenotypic presentation.
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.
3. Robinson PN, Booms P, Katzke S, et al: Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies. Hum Mutat 2002;20(3):153-161