Patient-specific iPS (induced pluripotent stem) cells are seen as key to modelling genetic disorders and developing new treatments for them. Now iPS cell lines have been generated by nuclear reprogramming from patients with LEOPARD syndrome, a rare developmental disorder characterized by skin lesions, heart abnormalities and deafness. Cardiomyocytes derived from the resulting LEOPARD iPS cells have hypertrophic properties resembling those typical of the disease — cardiac hypertrophy occurs in 90% of children with the syndrome. The reprogrammed cells feature extensive alterations in various signal transduction pathway components, including RAS–MAPK, some previously described in association with cardiac hypertrophy. Using these cell lines, together with robust differentiation protocols, it may be possible to identify compounds that reverse diseased cellular phenotypes. The generation of induced pluripotent stem cells (iPSCs) from patients with defined genetic disorders promises to help the basic understanding of complex diseases and the development of therapeutics. Here iPSCs have been generated from patients with LEOPARD syndrome, a developmental disorder with pleiomorphic effects on several tissues and organs. The iPSCs are characterized and the phenotype of cardiomyocytes derived from these cells is investigated. The generation of reprogrammed induced pluripotent stem cells (iPSCs) from patients with defined genetic disorders holds the promise of increased understanding of the aetiologies of complex diseases and may also facilitate the development of novel therapeutic interventions. We have generated iPSCs from patients with LEOPARD syndrome (an acronym formed from its main features; that is, lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary valve stenosis, abnormal genitalia, retardation of growth and deafness), an autosomal-dominant developmental disorder belonging to a relatively prevalent class of inherited RAS–mitogen-activated protein kinase signalling diseases, which also includes Noonan syndrome, with pleomorphic effects on several tissues and organ systems1,2. The patient-derived cells have a mutation in the PTPN11 gene, which encodes the SHP2 phosphatase. The iPSCs have been extensively characterized and produce multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. We show that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization and preferential localization of NFATC4 in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wild-type iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlate with a potential hypertrophic state. We also provide molecular insights into signalling pathways that may promote the disease phenotype.