Clinical Information

Fibrillin-1 is a 320 kDa, cysteine-rich glycoprotein found in the extracellular matrix. Monomers of fibrillin-1 associate to form microfibrils that 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.

Disease-causing FBN1 variants are most commonly associated with Marfan syndrome (MFS), an autosomal dominant connective tissue disease involving the ocular, skeletal, and cardiovascular systems. Ocular MFS manifestations most commonly include myopia and ectopia lentis (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 aneurysm and dissection, as well as mitral valve and tricuspid valve prolapse.(1) The clinical diagnosis of Marfan syndrome is based on the revised Ghent nosology for the Marfan syndrome.(2) There may be significant inter- and intrafamilial variability in the MFS phenotype.

Disease-causing FBN1 variants have also been reported in several other rare phenotypes with variable overlap with classic MFS.(3) In some cases, MFS may present in the neonatal period with severe, rapidly progressive disease (previously termed "neonatal Marfan syndrome"). Other FBN1-associated conditions include autosomal dominant ectopia lentis (displacement of the lens of the eye), isolated skeletal features of MFS, MASS phenotype (mitral valve prolapse, aortic diameter increased, stretch marks, skeletal features of MFS), autosomal dominant Weill-Marchesani syndrome (short stature, short fingers, ectopia lentis), Marfan lipodystrophy syndrome, and stiff skin syndrome.

Hundreds of disease-causing variants 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 disease-causing FBN1 variants. Approximately two-thirds of disease-causing FBN1 variants are missense changes, with the majority of these being cysteine substitutions. Approximately 25% to 33% of disease-causing FBN1 variants are de novo, in which an individual has no family history of disease. Disease-causing FBN1 variants have been shown to occur across the gene. Some genotype-phenotype correlations have been observed, including the association with truncating and splicing variants with risk for aortic dissection, cysteine-based variants associated with ectopia lentis, and severe, early onset MFS associated with variants in exons 24 through 32.(4-6)

Marfan syndrome has significant clinical overlap with a condition called Loeys-Dietz syndrome (LDS); however, the vascular phenotype of LDS can be more severe, and LDS has disease-causing variants in different genes (TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3). When the diagnosis of MFS, LDS, or a related disorder is suspected, the use of genetic testing is important to verify the diagnosis and provide appropriate clinical management. Single gene analysis of the FBN1 gene may be appropriate when there is a very high index of suspicion for Marfan syndrome based on clinical presentation and Ghent diagnostic criteria, while multigene panel-based testing can be more appropriate when the differential diagnosis includes Marfan syndrome and additional, overlapping phenotypes. Confirmation of the genetic diagnosis also allows for preconception, prenatal, and family counseling.