Clinical relevance of genotype-phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants

Abstract

Purpose: Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype-phenotype correlations have been found in proband studies only.

Methods: In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations.

Results: A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants.

Conclusion: This study shows that FBN1 genotype-phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.

Fig. 1. Kaplan–Meier estimated probabilities of the impact of the type of pathogenic variant in the FBN1 gene as a function of age.

Comparisons of survival (top), or aortic dissection or surgery (bottom). Left panel: all patients included in the study. Middle panel: patients with premature termination codon (PTC) (blue) vs. in-frame pathogenic variants (red). Right panel: patients with in-frame pathogenic variants associated with cysteine loss ([-Cys] in red), addition ([+Cys] in blue), or no fibrillin-1 protein cysteine content change ([noCys] in green).

Fig. 2. Kaplan–Meier estimated probabilities of the impact of a variant in the neonatal region (exons 24 to 32) vs. a variant located elsewhere in the FBN1 gene on aortic risk (dissection or surgery) according to age.

Comparison of variants located within the neonatal region (red) or elsewhere (blue) in the gene. Left panel: premature termination codon (PTC) (top), in-frame variants (bottom). Right panel: patients with in-frame pathogenic variants associated with (top) cysteine loss (-Cys), (middle) addition (+Cys), (bottom) no fibrillin-1 protein cysteine content change (noCys).

Fig. 3. Kaplan–Meier estimated probabilities of a male (blue) vs. female (red) sex effect as a function of age in the different subgroups of pathogenic variants in the FBN1 gene.

Left panel: premature termination codon (PTC) (top), in-frame variants (bottom). Right panel: (top) patients with in-frame pathogenic variants associated with cysteine loss (-Cys), (middle) addition (+Cys), (bottom) no change in the cysteine content change (noCys).

Fig. 4. Risk chart for genetic counseling of patients with heterozygous FBN1 pathogenic variants.

Percentage of patients with aortic event by the age of 40 to 80 years, ectopia lentis, scoliosis >20° according to their variant groups. Risk levels are illustrated by different colors (red: very high risk, orange: high risk, yellow: intermediate risk, and green: low risk). PTC premature termination codon.