Perspective:

The following are 10 points to consider from this review:

1. As DNA sequencing costs continue to decrease, screening for informative DNA variants in patients who may be at risk for a particular disease is becoming increasingly feasible. Screening for fibrillin (FBN)-1 gene variants may aid in the management of patients at risk for aortic diseases.

2. Mutations in the FBN-1 gene are associated with Marfan syndrome and other aortic diseases. The mechanisms responsible for FBN-1 effects on aortic diseases are complex and vary with specific mutations.

3. Most aneurysmal thoracic aortic disease is sporadic; however, 19% of subjects with a thoracic aorta dissection have an affected first-degree relative. A genome-wide association study (GWAS) of patients with sporadic thoracic aortic aneurysm (TAA) and dissection identified five significant single nucleotide polymorphism associations, all of which were in the region of the FBN-1 locus.

4. Bicuspid aortic valve (BAV) is the most common congenital heart defect occurring in 1-2% of the general population, and is associated with TAAs/dissection and Marfan syndrome. GWAS have implicated the FBN-1 locus in TAAs associated with BAV.

5. Marfan syndrome is an autosomal-dominant systemic disorder of connective tissue with prevalence of 1 per 5,000. By 60 years of age, 96% of Marfan syndrome patients develop ascending aortic dilatation, and 74% will either suffer dissection or undergo surgery.

6. FBN-1 mutations responsible for Marfan syndrome are distributed throughout the gene, but the most prevalent are missense mutations affecting a calcium binding endothelial growth factor domain. Identification of FBN-1 mutations may aid in the diagnosis of Marfan syndrome when equivocal phenotypes are present.

7. Transforming growth factor-beta (TGF-β) activation appears to play a critical role in Marfan syndrome since FBN-1 is a regulator of TFG-β activity and mutations in receptors for TGF-β are sufficient to cause Marfan syndrome.

8. Blockade of angiotensin 2 receptor type 1 (AT1) with losartan reduced TGF-β signaling and reduced aneurysm formation in murine models of Marfan syndrome. Treatment with losartan has shown to be effective in a small pediatric population with Marfan syndrome, although larger studies are needed.

9. Identification of specific FBN-1 mutations in Marfan patients may identify patients most likely to benefit from angiotensin-receptor blocker treatment.

10. Multiplex genotyping of known sequence variants of FBN-1 can be readily and inexpensively obtained, but are not yet commercially available. Complete FBN-1 gene sequencing will eventually become the standard.