Renal hypodysplasia (RHD) is a congenital malformation of the kidney often associated with additional malformations and clinical complications. Overall, kidney and urinary tract malformations main complication is end-stage kidney failure (ESRD), and they account for up to 50% of pediatric and 7% of adult ESRD worldwide. The biological basis of RHD is poorly understood. Currently rare variants in known genes (single nucleotide variants and small insertion deletion variants, or SNVs) and rare copy-number variants (CNVs) only explain the cause of 10-20% of RHD, limiting the development of optimal diagnostic and prognostic tools. Interestingly, our preliminary data suggest that common variants are significantly associated with kidney and urinary tract malformations, pointing to another mechanism to resolve the missing heritability of RHD. The central hypothesis of this application is that comprehensive genetic approaches can advance our understanding of the biological basis of RHD. The rationale underlying the application is that all types of genetic variants (common and rare, SNVs and CNVs, de novo and inherited) can cause RHD, and that some of the comorbidities associated with RHD can help identify novel genes associated with syndromic RHD. To ensure a comprehensive analysis, we will pursue three aims: 1) As de novo variants are known to be an important mechanism for developmental disorders, we will analyze the burden of all types of de novo variants (SNVs, CNVs and non-coding variants). 2) As both inherited and de novo mutations contribute to RHD and have pleiotropic effects on the development of other organs, we will also utilize case-control approach. To increase our statistical power, we will then combine the results from the case-control analysis with the results from the de novo analysis, and take advantage of the large publicly available sequenced cohorts of patients with RHD comorbidities to perform a combined case-control analysis. 3) We will test whether common variants can increase the risk for RHD by performing genome-wide association analysis on a large set of cases and controls, and calculating a polygenic risk score to predict RHD (RHD- PRS). We will then analyze the association between the RHD-PRS to its comorbidities, and examine whether the RHD-PRS can modify the effect of rare pathogenic variants. Taken together, this application will investigate variation across a range of allele frequencies, to better understand their contribution to pleiotropy, penetrance and clinical severity of disease. The project benefits from the researchers expertise in Human Genetic, large cohorts of RHD cases, and recent support from the NIH X01 program for whole genome sequencing.

Public Health Relevance

Kidney and lower 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 genetics 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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Genetics of Health and Disease Study Section (GHD)
Program Officer
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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