# Whole Genome Sequencing for Nephrotic Syndrome Discovery

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $552,820

## Abstract

Abstract
 Primary nephrotic syndrome (NS) is a rare disease of glomerular filtration barrier failure that causes
massive urinary excretion of protein. Morbidity and mortality from NS is related both to the disease and the non-
specific medications used to try to treat it. NS is currently classified and treated according to histologic
appearance (e.g. focal segmental glomerulosclerosis [FSGS], minimal change disease[MCD]) or response to
steroid therapy. This descriptive taxonomy is nonspecific and does not illuminate NS's underlying pathobiology.
To achieve increasingly precise and effective care for NS patients, a better understanding of its underlying
molecular mechanisms is necessary. Human genetics studies in NS have proven a promising strategy to permit
patient classification by molecular subtype and identify targets that will spur biomarker and drug discovery.
 To discover novel, and identify known, genetic determinants of NS, their clinical correlates, and the
mechanisms by which they confer their harm, we are generating and analyzing deep whole genome sequencing
and RNA-seq derived transcriptomic data from affected patients in a North American, population-based cohort.
Using gene expression from the kidneys of patients with NS, we aim to discover genetic variants associated with
NS via expression quantitative trait loci (eQTL) studies. Using eQTLs as an intermediate molecular phenotype
improves power to detect significant associations and will also directly illuminate biologic pathways that would
not have been detected otherwise. We will also determine the prevalence of known monogenic forms NS in this
cohort using robust bioinformatics filtering paired with functional testing. We will describe clinical correlates via
integration with baseline and longitudinal phenotyping. Beyond the polygenic model, we are equally determined
to discover the penetrance of the immunosuppressant resistant phenotype among patients with Mendelian NS.
 Our lab has thus far performed preliminary eQTL and Mendelian studies on enrollees in the Nephrotic
Syndrome Study Network, with promising results. Here, we will expand these studies, beginning in Aim 1 by
using new WGS and RNA-seq datasets to discover glomerular and tubulointerstitial eQTLs and identify those
specific to these kidney tissues vs other tissues. In Aim 2, we will localize these eQTLs to specific cell lineages
via integration with single cell RNA-Seq data, identify those overlapping kidney-derived regulatory regions, and
discover their association with biologic processes and clinical phenotypes. We will functionally test top candidate
eQTLs in drosophila and kidney organoid systems. In Aim 3, we will use WGS data to discover the prevalence
of NS due to known Mendelian causes. We will study clinical correlates of Mendelian NS in US patients and
identify factors associated with complete remission among those with Mendelian disease. Finally, we will use the
drosophila and organoids models to functional...

## Key facts

- **NIH application ID:** 10020397
- **Project number:** 5R01DK119380-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** MATTHEW Gordon SAMPSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $552,820
- **Award type:** 5
- **Project period:** 2019-09-18 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020397

## Citation

> US National Institutes of Health, RePORTER application 10020397, Whole Genome Sequencing for Nephrotic Syndrome Discovery (5R01DK119380-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10020397. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*