Disorders of the renal and urogenital system represent a major health burden, remain poorly understood, and are often clinically intractable. Of equal importance, anatomical defects in these organs are associated frequently with serious, life-threatening systemic syndromes that can remain refractive to diagnosis. The mission of our Center is to bring together cutting-edge genomics tools and interpretative biological assays to potentiate and accelerate the molecular diagnosis of these disorders. We propose three major activities: a) to phenotype, recruit and biobank samples from families recruited at the Duke clinics but also referred to us from across the United States with congenital anatomical renal and urogenital defects that have failed to secure a molecular diagnosis through traditional means; b) to perform exome (and ultimately genome) sequencing on appropriate family members;c) to functionally test a subset of discovered variation that is of predicted clinical value and to develop in vitro (primary cells) and in vivo tools (zebrafish and mouse) to model the effects of such variation; d) to synthesize hybrid clinical and research data that, in collaboration with the clinical management team, can inform future management and intervention in patients. In parallel, we propose two high-risk pilot activities aimed at improving both the genetics and the discovery of novel therapeutic leads. First, we will develop the technology for the rapid identification of new zebrafish renal mutants that can accelerate the identification of new genes important in kidney development. Second, we will generate new platforms for the screening of lead compounds in zebrafish models of renal disease (both previously established and newly-developed as part of our Center). Finally, because our Center represents a collaboration between patients, physicians and basic scientists, we will develop information platforms to facilitate the dissemination of exome-wide research and clinical data to both physicians and patient families, and to learn iteratively from this community about how to best implement such information to improve health care. Taken together, our Center will provide a much-needed niche in the field, will likely improve the knowledge base of both physicians and patients about syndromes with a renal and urogenital component, and will provide the foundation for accelerated diagnosis, management and treatment.
Technological advances in genomics have potentiated the rapid identification of genetic lesions whose functional interpretation can provide rapid diagnosis and focused clinical management. Our Center will generate and implement multidisciplinary tools to execute bedside-to-bench and back-to-bedside activities to improve information and health outcomes for children and families who have been unable to secure molecular diagnosis through traditional means.
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|Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel et al. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 376:742-754|
|Frosk, Patrick; Arts, Heleen H; Philippe, Julien et al. (2017) A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis. J Med Genet 54:490-501|
|Shaw, Natalie D; Brand, Harrison; Kupchinsky, Zachary A et al. (2017) SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49:238-248|
|Ta-Shma, Asaf; Khan, Tahir N; Vivante, Asaf et al. (2017) Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome. Am J Hum Genet 100:666-675|
|Ozantürk, Ay?egül; Davis, Erica E; Sabo, Aniko et al. (2016) A t(5;16) translocation is the likely driver of a syndrome with ambiguous genitalia, facial dysmorphism, intellectual disability, and speech delay. Cold Spring Harb Mol Case Stud 2:a000703|
|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|
|Lindstrand, Anna; Frangakis, Stephan; Carvalho, Claudia M B et al. (2016) Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome. Am J Hum Genet 99:318-36|
|Katsanis, Nicholas (2016) The continuum of causality in human genetic disorders. Genome Biol 17:233|
|Jordan, Daniel M; Frangakis, Stephan G; Golzio, Christelle et al. (2015) Identification of cis-suppression of human disease mutations by comparative genomics. Nature 524:225-9|
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