Phenotypical variability beyond the genotype/phenotype correlation in patients with FBN1 pathogenic variant

Abstract Introduction Marfan syndrome (MFS) is associated with the presence of a pathogenic variant in FBN1. The severity of aortic disease in these patients is highly variable despite the presence of a single mutated gene. Some patients have aortic dissection or require preventive aortic root surgery at an early age, while others have only mildly dilated aortas at an older age and never need surgery. This variability is partly explained by genotype-phenotype correlations. However, even patients with the same FBN1 variant can show significant differences in aortic severity. The extent of phenotypic variability within such groups remains unclear due to the limited number of patients with identical variants. In MFS, many variants lead to the formation of an early stop codon, resulting in premature termination of DNA transcription to RNA. The shorter RNA is degraded by nonsense-mediated mRNA decay system without being translated into fibrillin. Therefore, the biological consequence of these variants is similar, haploinsufficiency, and patients can be grouped as having an identical biological alteration. Phenotypic variability not related to genotype/phenotype correlation can then be tested. Methods and results From the 2091 patients with FBN1 pathogenic variants present in our biobank, we selected the 493 patients with variants leading to haploinsufficiency. The mean age at the last visit was 34.44±16.2, 230 were male, 62 had had aortic dissection (37 type A, 23 type B, 2 abdominal dissections ) and 146 had had preventive aortic root surgery. We then plotted the occurrence of aortic dissection or prophylactic aortic surgery by age separately for men and women. Consistent with our findings in the general MFS population, aortopathy was more severe in males (mean age at aortic event 32.2±9.3years in men vs 36.6±10.5 years in women). We defined a "severe" group as men with an aortic event (either aortic dissection or prophylactic aortic root surgery) occurring early (figure 1). We also plotted the last aortic diameter as a function of age in patients without aortic surgery and selected the oldest patients with lower diameters, corresponding to the dots on the graph (figure 2). Conclusion Thanks to this approach, we now have a biologically homogeneous cohort of MFS patients (haploinsufficiency), with a subgroup of severely affected males and females, a subgroup of only mildly affected males and females, which will be used to study modifiers. Identifying such modifiers could help develop strategies to mitigate or prevent aortic complications in MFS patients. Figure 1: number of type A aortic dissection as a function of age. The more severe patients are on the left of the graph Figure 2: aortic diameter as a function of age in patients without aortic surgery or dissection. The less severe patients are on the right of the graph