Impact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome
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Background: Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death).
Methods: We evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death).
RESULTS: The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; P<0.001). Male patients were at a greater than two-fold increased risk in both genotypes. In addition, after identifying deleterious variants among DN patients, we found that those with variants affecting or creating Cysteine residues and in-frame Deletion variants in exons 25–36 and 43–49 (DN-CD group) had a 6.3-fold higher risk compared with DN-nonCD patients (P<0.0001), which was comparable to or more deleterious than HI patients (P=0.062). Furthermore, DN-CD + HI patients had larger aortic root Z-scores than DN-nonCD patients (P<0.05 for <20 years; P<0.01 for 20–40 years), and males under 20 years old were more likely to develop aneurysms with higher rate of change in Z-score than females (P<0.001 in males; P=0.24 in females).
Conclusions: DN-CD+HI patients should be monitored more carefully than DN-nonCD patients for rapid development of aortic root aneurysms.
- © 2018 American Heart Association, Inc.