# Integration of genomics and transcriptomics to investigate biological pathways in very early onset IBD

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $650,288

## Abstract

ABSTRACT
The genomic contribution to the development of very early onset inflammatory bowel disease (VEO-IBD), IBD
diagnosed at <6 years of age, remains understudied, yet elucidation of genetic risk factors would undoubtedly
enhance our understanding of pathogenesis and suggest novel therapeutic approaches. The aggressive
phenotype, often refractory to conventional therapy, early onset, and strong family history points to an enrichment
of monogenic defects. Indeed, we and others have identified causal variants in VEO-IBD that has changed care
for these children. Whole exome sequencing has radically changed our approach to VEO-IBD, however, it has
only been successful in ~18% of cases, despite evidence highly suggestive of an underlying genetic defect. In
addition, linking the identified variant to the development of the VEO-IBD phenotype remains difficult.
The goal of this proposal is to widen our genetic analysis through whole genome sequencing (WGS) and
leverage transcriptome modifications to enhance our capacity in identifying causal variants. Our central
hypothesis is that a proportion of VEO-IBD is a monogenic disease, a subset of which will alter gene transcription,
and transcriptome analysis, including single cell analysis, will allow us to more rapidly and accurately identify
such mutations among the detected candidate variants. Using a novel innovative method, based on WGS, we
will expand our repertoire of causal defects in VEO-IBD. We will integrate these findings with RNA-seq and
scRNA-seq data, which can generate a more sensitive and specific approach to detect causal variants and
characterize their mechanism of action. In addition, when WGS cannot identify a clear causal variant, RNA-seq
and scRNA-seq can provide insight into the underlying disease mechanism, supporting the implication of
candidate mutations.
To test our central hypothesis, in Specific Aim 1 we will expand our dataset of potential causal mutations in VEO-
IBD through WGS. We will validate candidate genes in additional VEO-IBD cases. In Specific Aim 2, we will test
the ability of transcriptional profiling of colonic tissue and PBMCs to enhance the identification of novel causal
variants of VEO-IBD. Finally, in Specific Aim 3, using scRNA sequencing, we will assess the colonic and immune
cell heterogeneity and characterize genes and pathways associated with infantile onset IBD using transcriptional
profiling of individual cells from colonic tissue and PBMCs.
Completion of this project will result in the identification of novel genetic causes of VEO-IBD, providing a fertile
source of biologic processes to pursue to better understand the basic mechanisms of disease, with the ultimate
goal of translating this knowledge into improved care for children with VEO-IBD through individualized and
targeted therapy.

## Key facts

- **NIH application ID:** 10831996
- **Project number:** 5R01DK127044-04
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Judith Rachel Kelsen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $650,288
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831996

## Citation

> US National Institutes of Health, RePORTER application 10831996, Integration of genomics and transcriptomics to investigate biological pathways in very early onset IBD (5R01DK127044-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831996. Licensed CC0.

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