A successful transition to clinically valid genome-wide analyses of patients relies on a number of components that include: a) the application of robust bioinformatics tools for filtering exome- and genomewide variation data;b) evaluation of variation in physiologically relevant systems;and c) successful transmission of the information to physicians in a manner that can be understood (including limitations) and that can enable actionable recommendations. Project 2 will integrate state-of-the-art technology with functional testing to improve the interpretive power of exome- and genome-wide variation. We propose three Aims. First, we will implement computational analytical tools to identify novel variants discovered in patients with congenital renal and/or urogenital anatomical defects recruited as part of the present P50 w/ho have not been able to secure a molecular diagnosis by investigating known disease genes. Second, we will develop and implement malleable, physiologically relevant in vivo models to test the functionality of candidate pathogenic variants discovered in patients. Using zebrafish embryos, we will suppress or overexpress (depending on the patient genetic model) novel candidate disease genes and ask whether a) candidate gain of function or dominant negative mutations can induce phenotype upon expression of mutant mRNA;or b) whether point mutations can rescue the phenotype established by morpholino-based suppression of endogenous transript. Finally, we will explore the biochemical consequences of candidate pathogenic alleles on protein function using an array of in vitro systems that include transformed cell lines and primary cells derived from patients to seek further support for allele causality in children and neonates with insufficient genetic resolution. Our work will complement the overall Center mission of integrating genome-wide clinical and research investigations to understand the molecular pathogenesis of complex renal and urogenital pathologies, will provide insights on the cellular basis of disease, and will generate in vivo and in vitro models that can be applied to the development and testing of therapeutic paradigms.
Despite significant progress, the interpretation of variation found in exome and genome data often remains an intractable problem. Project 2 will generate and implement tools to test biologically the effect of candidate pathogenic variation and provide evidence of causality that will accelerate gene discovery, offer initial insight into disease mechanism and generate assays suitable for pharmacological screens.
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|Bolar, Nikhita Ajit; Golzio, Christelle; Živná, Martina et al. (2016) Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia. Am J Hum Genet 99:174-87|
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