Genotype-phenotype correlations in Marfan syndrome patients with FBN1 mutations: a cohort study on 1575 patients

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Abstract Background 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 probands' studies only. Purpose The aim of this study is to provide survival curves and genotype-phenotype correlations in all patients with FBN1 mutations, probands and relatives. Methods We established survival curves and sought genotype–phenotype correlations in a population of 1575 consecutive MFS patients with pathogenic class 4 or 5 variants in the FBN1 gene. This population represents the most comprehensive clinical database worldwide on MFS. Results Global survival was 90% at 60 years. However, lifelong aortic event rate (either dissection or surgery) and survival were impacted by the genotype. Premature termination codons (PTC), resulting in haploinsufficiency, were associated with a shorter life expectancy and a high lifelong risk of an aortic event (83%). Interestingly, these variants were also associated with the highest risk of severe scoliosis (52%) and with a lower risk for ectopia lentis (EL) surgery (13%). Dominant negative in-frame pathogenic variants could be subdivided according to their impact on the cysteine content of fibrillin-1: cysteine loss (–Cys) was associated with high aortic risk (73%) and a higher frequency of EL surgery (43%); cysteine addition was associated with moderate aortic risk (29%) and the highest frequency of EL surgery (48%); unchanged cysteine content was associated with high aortic risk (61%) and lower frequency of EL surgery (23%). No gene-region effect was observed, except for a more severe phenotype for in-frame variants with cysteine loss within the “neonatal region”. Aortic risk was greater for males in all subgroups, and probands were more severely affected. Conclusions MFS genotype-phenotype correlations related to pathogenic FBN1 variants exist for aortic and extra-aortic features. This leads us to propose new tools to refine the prognosis in this population. Preventive therapy with β-blockers and restricted exercise should be proposed regardless of the aortic diameter in the high aortic risk groups (PTC and –Cys variants). These results have major consequences on genetic counseling and personalized medicine for patients carrying a FBN1 mutation. This study also improves the overall understanding of the role of FBN1 in various organs. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Fondation Coeur et Recherche, Paris, FranceFédération Française de Cardiologie, Paris, France Patients with PTC vs. in-frame mutationsDifferences within in-frame mutations

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