The goals of this project are to apply genetic approaches to resolve the biology of kidney malformations. Kidney and urinary tract malformations account for up to 50% of pediatric end-stage kidney failure worldwide. They are highly heterogeneous in manifestation and outcome, and the biological basis of these disorders is poorly understood, limiting the development of optimal diagnostic and prognostic tools to improve clinical management. During the last funding cycle, we achieved considerable progress in resolving the genetic architecture and biology of kidney malformations. We found that pathogenic copy number variants (CNVs) are a common (10.5% of the cohort) and overlooked cause of kidney malformations. Applying exome sequencing, we defined a new syndrome caused by mutations in Dual Serine-threonine and Tyrosine Kinase (DSTYK) in 2.3% of children with urinary tract malformations. Altogether, our studies suggest that point mutations or CNV disorders can explain 25-30% of congenital kidney defects and provide many novel opportunities for clinical and basic investigations. Here, we now propose to extend these studies in a large cohort of patients with kidney malformations.
In aim 1, we will develop a comprehensive map of genomic structural variants contributing to kidney malformations and define candidate genes.
In aim 2, we will define additional candidate genes for kidney malformations via analysis of exome data from 100 index cases from multiplex families and 50 trios derived from sporadic cases.
In aim, we will comprehensively model variants in zebrafish and confirm novel genes for kidney malformation by screening for independent mutations in the full cohort using Molecular Inversion Probe resequencing. Finally we will perform genotype/phenotype correlations to aid in the characterization and workup for patients with kidney malformations.

Public Health Relevance

Kidney and urinary tract malformations account for up to 50% of pediatric end-stage kidney failure worldwide. If successful, this project will bring significant progress in understanding the genetic architecture of kidney malformations, elucidate biological pathways and introduce genomics into personalized clinical care for these patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Parsa, Afshin
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Sanna-Cherchi, Simone; Westland, Rik; Ghiggeri, Gian Marco et al. (2018) Genetic basis of human congenital anomalies of the kidney and urinary tract. J Clin Invest 128:4-15
Winawer, Melodie R; Griffin, Nicole G; Samanamud, Jorge et al. (2018) Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 83:1133-1146
Groopman, Emily E; Rasouly, Hila Milo; Gharavi, Ali G (2018) Genomic medicine for kidney disease. Nat Rev Nephrol 14:83-104
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
Verbitsky, Miguel; Kogon, Amy J; Matheson, Matthew et al. (2017) Genomic Disorders and Neurocognitive Impairment in Pediatric CKD. J Am Soc Nephrol 28:2303-2309
Verbitsky, Miguel; Sanna-Cherchi, Simone; Fasel, David A et al. (2015) Genomic imbalances in pediatric patients with chronic kidney disease. J Clin Invest 125:2171-8
Prakash, Sindhuri; Gharavi, Ali G (2015) Diagnosing kidney disease in the genetic era. Curr Opin Nephrol Hypertens 24:380-7
Materna-Kiryluk, Anna; Kiryluk, Krzysztof; Burgess, Katelyn E et al. (2014) The emerging role of genomics in the diagnosis and workup of congenital urinary tract defects: a novel deletion syndrome on chromosome 3q13.31-22.1. Pediatr Nephrol 29:257-67
Sanna-Cherchi, Simone; Sampogna, Rosemary V; Papeta, Natalia et al. (2013) Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med 369:621-9

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