Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with pleiotropic ocular, skeletal and cardiovascular manifestations. Morbidity and mortality are mostly determined by aortic root aneurysm, dissection and rupture. Although mutations in FBN1, coding for fibrillin-1, are the sole genetic MFS cause, there is a poor correlation between the MFS phenotype and the nature or location of the FBN1 variant. Wide intra- and interfamilial phenotypic variability, ranging from completely asymptomatic to sudden death at young age, is observed. The precise mechanisms underlying this variability remain elusive. In this project, we have selected an innovative strategy to fully understand the functional effects of the FBN1 mutation and discover genetic modifiers of MFS aortopathy with the following objectives: (1) CRISPR/Cas9 correction of the recurrent FBN1 p.Ile2585Thr in patient-derived iPSC-VSMCs and functional comparison to FBN1 mutant and control iPSC-VSMCs. (2) Whole genome and RNA-sequencing of patient iPSC-VSMCs at the extreme ends of the phenotypical spectrum for genetic modifier identification. (3) CRISPR-modification for validation of their modifying capacities. The understanding of the functional effects of the FBN1 mutation and the identification of genetic modifiers will advance the knowledge on aortopathy-mechanisms beyond current understanding, it will allow to individualize treatment protocols and will offer new leads to novel therapeutic targets.