# An in vivo platform to characterize variants associated with congenital pediatric disorders

> **NIH NIH R03** · WASHINGTON UNIVERSITY · 2021 · $118,125

## Abstract

PROJECT SUMMARY
Clubfoot is one of the most common structural birth defects with a prevalence of 1 in 1000 live births world-
wide. Therapeutic options for children born with clubfoot are limited to supportive care including skeletal
bracing and invasive surgical interventions. If left untreated, which is common in low- to middle- income
countries that lack specialized institutional management, clubfoot can incur lifelong economic, social, and
physical burdens. The genetic causes of clubfoot are not confined to a single locus and pathogenic variants
have been identified in B3GAT3, CHST14, CHST3, COG4, MYBPC1, MYH3, PITX1, and TPM2. Large-scale
sequencing initiatives have identified countless variants in clubfoot-associated loci, but a vast majority of these
variants remain uncharacterized.
From a developmental standpoint, the genes associated with clubfoot control the morphogenesis of multiple
systems including bone, muscle, and connective tissues, and the disease mechanisms contributing to clubfoot
likely involve incomplete or inappropriate interactions among multiple organs. Our overarching hypothesis is
that understanding and ultimately treating disorders involving clubfoot will require in vivo models that can
validate variant pathogenicity and uncover the affected developmental programs that promote disease. By
leveraging the speed and versatility of zebrafish genetics, we will screen variants of unknown significance
(VUS) identified in patients with clubfoot-associated disorders and use pathogenic variants to further model
disorders.
Distal Arthrogryposes (DA) are a group of related disorders characterized by contractures, which are defined
as a permanent shortening of muscles and joints that inhibit limb movement and function. Clubfoot is one
diagnostic feature of DA, but affected patients often show involvement outside the extremities including
craniofacial defects and scoliosis. Pathogenic Tropomyosin 2 (TPM2) variants are causative of DA, but a large
number of uncharacterized TPM2 variants have been identified in DA patients. As an entry point to modeling
DA, we will (1) use zebrafish embryos as a screening platform to characterize fourteen VUS in TPM2, and (2)
perform comparative longitudinal studies of three pathogenic TPM2 variants. We expect that these proof-of-
principle studies will show that defects in muscle development lead to dysfunctional assembly of the
musculoskeletal system, and in turn to the contractures associated with clubfoot and structural birth defects.
Our long-term goals are to use the methods developed in this application to study variants in an array of loci
associated with DA, and to identify small molecules that ameliorate variant pathogenicity.

## Key facts

- **NIH application ID:** 10109908
- **Project number:** 1R03HD104065-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Christina Gurnett
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $118,125
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109908

## Citation

> US National Institutes of Health, RePORTER application 10109908, An in vivo platform to characterize variants associated with congenital pediatric disorders (1R03HD104065-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10109908. Licensed CC0.

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