# An integrative approach to understanding the genetic basis of very early onset inflammatory bowel disease

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $256,959

## Abstract

The genomic contribution to the development of very early onset inflammatory bowel disease (VEO-IBD), or 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. Patients with VEO-IBD
often present with greater extent and severity of disease than older onset IBD. Traditional therapies with
immunosuppression often fail and in cases of immune deficiencies, are inappropriate. The aggressive
phenotype, early onset, and strong family history points to an enrichment of monogenic defects in VEO-IBD.
Indeed, we and others have identified causal genetic variants in VEO-IBD. Whole exome sequencing (WES) has
radically changed our approach to VEO-IBD. However, linking the WES identified variant to the development of
the VEO-IBD phenotype remains difficult. The goal of this proposal is to expand the repertoire of highly penetrant,
causal variants responsible for VEO-IBD through a large scale sequencing study of a well characterized patient
cohort, followed by replication in independent cohorts and functional validation of some of the identified variants.
Our central hypothesis is that single gene defects are responsible for a large proportion of cases with VEO-IBD,
and they can be effectively characterized by a multidisciplinary approach starting from state-of-the-arts genomic
studies. In addition, we will test whether the identified VEO-IBD genes and pathways are specific to early onset
cases or are also involved in susceptibility to the more common form of older onset IBD. Finally, we will
specifically test the hypothesis that causal variants in specific genes and pathways will be associated with
changes in the gut microbiome composition that will support their role in VEO-IBD. The rapidly increasing
incidence of VEO-IBD cannot be explained by genetic susceptibility alone, and suggests a role of the gut
microbiota as a driver of disease. To test our central hypothesis, in Specific Aim 1 we will create a dataset of
potential causal mutations in VEO-IBD patients by WES. Our preliminary data using WES in VEO-IBD has
already identified causal variants confirming the enrichment of monogenic defects in VEO-IBD. We will now
increase our sample size to create a large catalogue of candidate genes that we will validate in additional
independent VEO-IBD cases, and test for association with older onset IBD. In Specific Aim 2, candidate VEO-
IBD variants will be subject to functional studies to confirm their causal effects. Finally, in Specific Aim 3, we will
correlate data obtained from our parallel study “The Microbiome in VEO-IBD” with the genomic data of Aim 1 to
look for changes in the microbiota associated with the defects in the different pathways leading to VEO-IBD.
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 b...

## Key facts

- **NIH application ID:** 10005948
- **Project number:** 5R01DK111843-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Judith Rachel Kelsen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $256,959
- **Award type:** 5
- **Project period:** 2018-09-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005948

## Citation

> US National Institutes of Health, RePORTER application 10005948, An integrative approach to understanding the genetic basis of very early onset inflammatory bowel disease (5R01DK111843-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10005948. Licensed CC0.

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