Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events

Purpose: Marfan syndrome is a systemic disorder that typically involves FBN1 mutations and cardiovascular manifestations. We investigated FBN1 genotype–phenotype correlations with aortic events (aortic dissection and prophylactic aortic surgery) in patients with Marfan syndrome. Methods: Genotype and phenotype information from probands ( n = 179) with an FBN1 pathogenic or likely pathogenic variant were assessed. Results: A higher frequency of truncating or splicing FBN1 variants was observed in Ghent criteria–positive patients with an aortic event ( n = 34) as compared with all other probands ( n = 145) without a reported aortic event (79 vs. 39%; P < 0.0001), as well as Ghent criteria–positive probands ( n = 54) without an aortic event (79 vs. 48%; P = 0.0039). Most probands with an early aortic event had a truncating or splicing variant (100% ( n = 12) and 95% ( n = 21) of patients younger than 30 and 40 years old, respectively). Aortic events occurred at a younger median age in patients with truncating/splicing variants (29 years) as compared with those with missense variants (51 years). A trend toward a higher frequency of truncating/splicing variants in patients with aortic dissection ( n = 21) versus prophylactic surgery ( n = 13) (85.7 vs. 69.3%; not significant) was observed. Conclusion: These aortic event– and age-associated findings may have important implications for the management of Marfan syndrome patients with FBN1 truncating and splicing variants. Genet Med 17 3, 177–187.