# Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery

> **NIH NIH RC2** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $1,474,145

## Abstract

SUMMARY The four lead investigators of this project have assembled ~10,000 patients with focal and
segmental glomerulosclerosis (FSGS) and steroid-resistant nephrotic syndrome (SRNS). With this largest
ever FSGS/NS cohort assembled, the vast majority whom have already undergone genome-wide sequencing,
we propose a collaborative effort to understand the genetic basis of this disease. The increasing number of
identified genes that can cause FSGS/SRNS when altered shows that these phenotypes are genetically highly
complex. Understanding the genetic basis of FSGS and NS is important: (1) Work to date has been the major
driver in understanding the molecular structure of the glomerulus; (2) Genetic diagnosis affects therapy: some
mutations predict lack of response to steroid therapies, others predict response to nutritional supplementation;
(3) Genetics affects renal transplant planning and outcome. Major gaps remain: (1) Most FSGS/NS cases still
are genetically unresolved; (2) The basis of disease is complex and involves the contribution of different
variants across the spectrum of allelic frequency and penetrance; (3) Our ability to declare genetic causality at
the single-patient level is limited; (4) Therapeutic options are limited. Thus, we will use this large cohort and
new analytic methods to address these gaps. We will functionally characterize many of the new alleles and
new FSGS genes that we discover. We will develop and distribute reagents, including patient-derived iPS cells.
We will create a database by aggregating exome and genome sequencing data from our patients, and make
this data available via web browser to assist the research community. We plan to: Aim 1: Understand the
spectrum of rare genetic variation that causes (or increases risk of) FSGS and NS in humans. By leveraging
large sample sizes, we can use approaches that are not otherwise powerful enough for disease gene
identification. We will discover novel genes associated with FSGS/NS to identify highly penetrant variants
(including burden tests of rare sequence changes and copy-number variants), define the spectrum of SNV and
structural variants in known FSGS/NS genes, and identify glomerular genes co-expressed with disease-related
genes. Aim 2: Define functional effects of disease-associated variants. We will test effects of
variants/mutations in cell-based assays, develop new zebrafish models by mutating FSGS/NS genes, and
generate a panel of iPS cells from patients with FSGS/NS-associated mutations. Aim 3: We will bring together
all of our genotyping data, generated from SNP arrays, WES, and WGS, to build and maintain a publicly
available variant browser, the “Nephrotic Syndrome Genomic Portal” (NSGP). NSGP will include allele
frequency data, functional classification, and clinical correlates for FSGS/NS. We will summarize, at a site-
level, SNVs, insertion-deletions, structural variants (CNV) observed in our FSGS/NS cohort and provide quality
metrics of variants reported. N...

## Key facts

- **NIH application ID:** 10441350
- **Project number:** 5RC2DK122397-03
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** FRIEDHELM HILDEBRANDT
- **Activity code:** RC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,474,145
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441350

## Citation

> US National Institutes of Health, RePORTER application 10441350, Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery (5RC2DK122397-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10441350. Licensed CC0.

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