Research Projects

Neurodevelopmental disorders (NDD) are caused by impairments in brain development and function resulting from genetic and environmental insults. A large number of genes have been identified as causal for NDDs and manifesting a diverse spectrum of phenotypes of which many are very rare. The shared clinical phenotypes of these disorders with common neurodevelopmental, neurological and psychiatric disorders, suggests their shared genetic etiology. However, mechanistic studies on rare NDDs caused by genetic aberrations are limited. Recently loss-of-function of Interferon regulatory factor 2 binding protein-like (IRF2BPL) gene has been identified as causal for severe NDD characterized by a remarkably similar pattern of neurodevelopmental regression, abnormal movements, loss of speech, and epileptic seizures. The majority of the cases also showed brain atrophy and neuronal migration deficits. To date, only 26 IRF2BPL-related NDD cases have been reported worldwide. However, the mechanistic role of IRF2BPL in neurodevelopment and its deficits in disease manifestation are largely unknown. Here we aim to model IRF2BPL-deficits in human induced pluripotent stem cells (hiPSC) and systematically characterize the neurodevelopmental phenotypes relevant for the disease and molecular pathogenesis during cortical neuronal development. The results obtained from this proposal will aid in understanding the complex genetic etiology of IRF2BPL–related NDDs and the associated phenotype spectrum. Characterizing molecular players for the disease pathogenesis will also help to identify leads for potential druggable therapeutic targets. Thus the results from the project will provide the basis for the mechanistic understanding of the IRF2BPL-related NDDs which will aid in the proper diagnosis, management and therapeutic targeting.