# INTEGRATIVE GENOMICS OF CHILDHOOD INTERSTITIAL LUNG DISEASE

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $844,386

## Abstract

Children’s Interstitial and Diffuse Lung Diseases (chILD) are disorders of the lung tissue that present in infancy
and early childhood. ChILD pose major burdens on thousands of children across the U.S., on their families, and
on the healthcare system more broadly. For most, the chILD-causing genes have not yet been identified and
current treatments are non-specific and are all too often ineffective. The long-term goal of this project is to define
the genetic landscape of chILD to inform the development of more specific and biologically rational therapies.
Our approach is informed by our implementation of two complementary approaches: (i) whole-exome
sequencing of patients seen in our chILD ambulatory clinics, which has to date established a genetic diagnosis
in 20% of cases, including discovery of 6 novel candidate chILD genes; and (ii) in situ gene expression profiling
of lung biopsy specimens, which we find differentiates samples with similar chILD histopathology based on their
underlying genetic causes, suggesting that patients with similar profiles may have forms of chILD caused by
shared molecular factors. In Aim 1, we will expand on these observations by profiling 300 available chILD lung
biopsy samples to define patient groups (clusters) with similar molecular profiles. A chILD molecular classifier
will be developed using 50 samples with definitive diagnoses and then validated in an independent set of 50
samples. The model will then be applied to 200 additional samples from patients lacking a molecular diagnosis
and assess the biologic significance of each cluster using gene set enrichment and rare variant genetic analyses.
We will assess clinical significance of cluster membership by testing for differences in clinical outcomes across
clusters. In Aim 2, we will analyze whole exome sequence data from a cohort of 400 children with unexplained
childhood parenchymal lung disease using family- and population-based methods to map new ChILD-causing
genes. To improve power, we apply integrative genomic and network-based analytic approach that incorporates
in situ transcriptomic data from Aim 1. We will replicate findings in the ChILD Research Network (ChILDRN)
registry and will evaluate the functional impact of candidate variants on target protein expression using patient-
derived biobanked samples. In Aim 3, to better understand how newly discovered ChILD genes contribute to
disease pathogenesis, and to characterize the spectrum of their clinical presentations, we will identify patients
harboring rare genetic variation in 6 novel chILD genes by screening the Genomic Information Commons (GIC)
database – an NIH-supported, federated infrastructure facilitating cross-institutional query of genotype–
phenotype databases at leading U.S. children’s hospitals. Children with these variants will be invited with their
parents to undergo standardized phenotypic assessments (clinical evaluations, biochemical analyses, and
molecular profiling) to characteriz...

## Key facts

- **NIH application ID:** 10981781
- **Project number:** 1R01HL170151-01A1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Benjamin Alexander Raby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $844,386
- **Award type:** 1
- **Project period:** 2024-08-26 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981781

## Citation

> US National Institutes of Health, RePORTER application 10981781, INTEGRATIVE GENOMICS OF CHILDHOOD INTERSTITIAL LUNG DISEASE (1R01HL170151-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10981781. Licensed CC0.

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