Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the gene coding for FIBRILLIN-1 (FBN1), an extracellular matrix protein. MFS is inherited as an autosomal dominant trait and displays major manifestations in the ocular, skeletal, and cardiovascular systems. Here we report molecular and phenotypic profiles of skeletogenesis in tissues differentiated from human embryonic stem cells and induced pluripotent stem cells that carry a heritable mutation in FBN1. We demonstrate that, as a biological consequence of the activation of TGF-β signaling, osteogenic differentiation of embryonic stem cells with a FBN1 mutation is inhibited; osteogenesis is rescued by inhibition of TGF-β signaling. In contrast, chondrogenesis is not perturbated and occurs in a TGF-β cell-autonomous fashion. Importantly, skeletal phenotypes observed in human embryonic stem cells carrying the monogenic FBN1 mutation (MFS cells) are faithfully phenocopied by cells differentiated from induced pluripotent-stem cells derived independently from MFS patient fibroblasts. Results indicate a unique phenotype uncovered by examination of mutant pluripotent stem cells and further demonstrate the faithful alignment of phenotypes in differentiated cells obtained from both human embryonic stem cells and induced pluripotent-stem cells, providing complementary and powerful tools to gain further insights into human molecular pathogenesis, especially of MFS. M arfan syndrome (MFS) is a heritable dominant disorder of fibrous connective tissue, caused by mutations in the gene encoding fibrillin-1 on chromosome 15 (1, 2). MFS shows striking pleiotropism and clinical variability (3, 4). Cardinal pathological features occur in three systems-skeletal, ocular, and cardiovascular (4-8)-and share overlapping features with congenital contractural arachnodactyly, which is caused by a mutation in the FIBRILLIN-2 (FBN2) gene (9). FBN1 mutations are detected in the majority of the patients fulfilling the clinical criteria, but also in incomplete phenotypes, referred to as type 1 fibrillinopathies (10). FBN1 is an extracellular matrix glycoprotein containing 43 calcium-binding EGF-like domains and 78 cysteine-containing TB motifs (11, 12). Mutations in FBN1 are the etiology of many phenotypes observed in MFS. The most common mutations found in FBN1 in MFS are missense mutations (56%), mainly substituting or creating a cysteine in a calcium-binding EGF-like domain. Other mutations are frameshift, splice, and nonsense mutations (13). There are only a few reports of patients with marfainoid features and a molecularly proven complete deletion of a FNB1 allele (14-16). Most of FBN1 deletions are associated with a severe or classical Marfan phenotype (17)(18)(19)(20). Although the molecular pathogenesis of MFS was initially attributed to a structural weakness of the fibrillin-rich microfibrils within the ECM, more recent results have documented that many of the pathogenic abnormalities in MFS are the result of alterations in TGF-β signaling (18,19). M...