# Genetics of human renal hypodysplasia

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $593,418

## Abstract

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.

## Key facts

- **NIH application ID:** 10241548
- **Project number:** 5R01DK080099-11
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ALI G GHARAVI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $593,418
- **Award type:** 5
- **Project period:** 2008-04-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241548

## Citation

> US National Institutes of Health, RePORTER application 10241548, Genetics of human renal hypodysplasia (5R01DK080099-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241548. Licensed CC0.

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