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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-G)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
United States
Zip Code
Tsai, I-Chun; McKnight, Kelly; McKinstry, Spencer U et al. (2018) Small molecule inhibition of RAS/MAPK signaling ameliorates developmental pathologies of Kabuki Syndrome. Sci Rep 8:10779
Sanna-Cherchi, Simone; Khan, Kamal; Westland, Rik et al. (2017) Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. Am J Hum Genet 101:789-802
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
Loviglio, Maria Nicla; Arbogast, Thomas; Jønch, Aia Elise et al. (2017) The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs. Am J Hum Genet 101:564-577
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
Katsanis, Nicholas (2016) The continuum of causality in human genetic disorders. Genome Biol 17:233

Showing the most recent 10 out of 32 publications