Genetic Insights in Hindbrain Abnormalities Through Network Analysis Expose Key Biological Pathways in Hindbrain Development

The number of known developmental disorders affecting the hindbrain is rapidly increasing due to advances in neuroimaging and genetic technologies. Nevertheless, it remains largely unknown why the development of the hindbrain is affected in many genetic disorders. We aim to unveil new insights into the biological pathways essential for hindbrain development by investigation of the pathogenetics of hindbrain abnormalities. In this work, an updated gene list of abnormalities of the hindbrain was generated, and genes were subsequently grouped according to most prevalent association in (1) predominantly cerebellar, (2) cerebellar and brainstem and (3) brainstem malformations. Brain-specific gene co-expression networks were generated to identify functional relationships and novel genes that were not yet linked to hindbrain malformations. The results showed that shared biological pathways underlie distinct hindbrain processes, even when cells originate from different primordia. Key players in hindbrain development include genes encoding transcription factors and extracellular signaling molecules. Notably, brainstem abnormalities are biologically distinct, with a smaller role for ciliogenesis. Through co-expression analysis, we identified candidate genes for hindbrain malformations including TRRAP and NCAM1. The identification of essential biological pathways in this study uncovers additional important challenges in genetic hindbrain malformations, such as how defects in apparently ubiquitous processes result in brain-specific phenotypes, and how timing and repair mechanisms influence the pathogenesis of affected pathways.