Seminar : Dissection of Pediatric Genetic Disease: Models, Modules and Understanding Phenotype

Abstract:

Variant data have been cataloged for millions of humans, representative of Mendelian disease cohorts, complex trait consortia, and healthy populations. This flood of information, expected to grow hyper-exponentially in the coming years, has already fueled the development of animal models to assign physiological relevance of genotype to phenotype; to inform variant pathogenicity; and to dissect multi-locus interactions. Here, we discuss our experience with the zebrafish model and its refined molecular toolkit to conduct scalable throughput analyses of novel disease genes implicated in rare pediatric disease in humans. We place particular emphasis on congenital anomalies in children impacting the structure of the brain, face, and kidney due to their direct anatomical surrogates in the developing zebrafish. Here, we highlight how our disease modeling work has enabled grouping of rare disease entities around molecular modules, discrete organelles, or cellular pathways.