The generation of induced pluripotent stem cells (iPSCs) from adult easily accessible somatic tissues was introduced ten years ago. This technology has revolutionized our opportunities to study human disorders including complex genetics and develop novel therapeutic concepts for regenerative medicine. By differentiating iPSCs to different cell types and stages, we can gain insights into developmental and disease driving molecular networks. Yet, a discussed question of the iPSC model system is the extent to which they retain residual phenotypes from their precursor, which impacts on the study of transcription networks. Moreover, it is open to which degree somatic mutations impact on functional studies of human genetic disorders when patient-specific iPSCs are applied. Here, we will tackle this question in the course of studying healthy and diseased siblings with Tetralogy of Fallot, a frequent congenital heart defect of multigenic origin. Routine genetic screenings are mainly based on genetic material derived from either whole blood or cheek swap sampling. ps-iPSCs are typically derived from dermal fibroblast (skin biopsies) or whole blood derived immortalized lymphoplastoid cell lines (LCLs). We will discuss whole genome frequency and impact of somatic acquired mutations on gene expression and functional studies of complex genetic disorders using ps-iPSCs.