Modeling Proteomic and Phenotypic Effects of DNA Copy Number Variants Using Stem Cell Approaches

DNA copy number variation, the gain or loss of DNA segments ranging from a few hundred base pairs up to millions of base pairs, has recently been recognized as an important source of normal genetic variation in humans. However, such CNVs have also recently been described to cause a number of human diseases, ranging from developmental delay to autism to congenital anomalies including cardiac, neurological, and musculoskeletal defects. Intriguingly, some patients who carry a pathogenic CNV have very severe clinical consequences, while their close relative may carry the same CNV with only a mild or even no apparent phenotype. The underlying mechanisms behind such "variable penetrance" remain largely unknown. We aim to use patient-derived samples to first investigate whether variation at the protein level - which cannot be detected using current DNA-based methods alone - may explain some of the variable penetrance between CNV carriers. Furthermore, we aim to generate new models to study and potentially treat CNVs by using CRISPR/Cas9 and induced pluripotent stem cell approaches.