Disorders of the kidney and urogenital tract represent a substantial fraction of anatomical defects in neonates and young children and pose a significant burden in families and the healthcare system. They require multiple medical, and sometimes surgical, interventions;they typically remain of obscure molecular etiology;and can be the harbinger of complex, syndromic, sometimes life-threatening conditions that manifest later in childhood and adolescence. Recent advances in genomic technologies offer a unique opportunity to study these disorders and to offer accurate and timely diagnosis that, in some instances, will help focus and/or redirect medical care, as well as provide support to families with affected children. Moreover, such genetic approaches are particularly attractive because past studies, typically on large families or extensive cohorts, have led to the identification of highly penetrant mutations, which have In turn illuminated disease pathomechanism. Project 1 aims to leverage the extensive infrastructure at the Duke Pediatric and Neonatal Clinics to establish a method by which we can utilize efficiently the information obtained from genomic studies to improve clinical evaluation and subsequent treatment of children with kidney and urogenital tract malformations. In addition, data from this study have the potential to help inform the cellular mechanisms governing genitourinary tract development and, through the dissemination of our findings both across this Center and to the scientific community, potentiate a range of new studies from basic biology to the development of new therapeutic paradigms. We propose two Aims. First, we will ascertain and perform detailed phenotypic characterization of an initial cohort of 50 children with syndromic and non- syndromic congenital anomalies of the kidney and the urinary tract and their parents. Second, we will perform whole exome sequencing to identify potential disease causing variants and to develop best practices for the return of both clinically-confirmed mutational data as well as hybrid clinical and research studies of sufficient confidence to physicians. These studies will inform the utility of whole exome sequencing in the clinical setting and potentiate rich research discovery for our Center and the broader community.

Public Health Relevance

Congenital renal and urogenital disorders contribute significantly to infant morbidity and mortality, and, despite the fact that they are known to be caused, in part, by penetrant mutations, the majority of patients with such phenotypes never receive molecular diagnoses. Project 1 will seek to implement cutting edge genomic technologies to improve such diagnoses and outcomes and to potentiate biological discovery.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Specialized Center (P50)
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Special Emphasis Panel (ZDK1-GRB-G)
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Duke University
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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
Ozantürk, Ayşegül; 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
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
Angrist, Misha (2015) Start me up: ways to encourage sharing of genomic information with research participants. Nat Rev Genet 16:435-6
Anderson, Blair R; Howell, David N; Soldano, Karen et al. (2015) In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress. PLoS Genet 11:e1005349
Burrage, Lindsay C; Charng, Wu-Lin; Eldomery, Mohammad K et al. (2015) De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. Am J Hum Genet 97:904-13
Bögershausen, Nina; Tsai, I-Chun; Pohl, Esther et al. (2015) RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome. J Clin Invest 125:3585-99
Bonora, Elena; Bianco, Francesca; Cordeddu, Lina et al. (2015) Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction. Gastroenterology 148:771-782.e11
Isrie, Mala; Breuss, Martin; Tian, Guoling et al. (2015) Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type. Am J Hum Genet 97:790-800

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