# Mechanisms of Abnormal Diaphragm and Cardiac Development

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $448,377

## Abstract

Project Summary
 Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that accounts for 8% of all major
congenital anomalies. In cases where CDH co-occurs with cardiovascular malformations (CVMs), mortality
rates increase from 30 to 60%, and long-term morbidity is common. Our goal is to identify genes that cause
CDH and CDH/CVM, and to discover the mechanism by which they control diaphragm and heart development.
 Correctly identifying genes that contribute to specific phenotypes from the large list of candidate genes
data generated in research and clinical studies is a major obstacle to progress in this and other research fields.
In Specific Aim #1, we will address this challenge by generating ranked CDH and CDH/CVM pathogenicity
scores for all RefSeq genes using a machine-learning algorithm that integrates data from large-scale genomic
knowledge sources. We will use these scores to identify novel CDH and CDH/CVM genes from cytogenetically
defined critical regions and form large next-generation sequencing databases as part of our multifaceted
approach to novel gene discovery. We will also accelerate the pace at which human disease genes are
discovered by making these scores and our machine-learning algorithm freely available.
 8p23.1 microdeletions that encompass GATA4 and SOX7 are among the most frequently identified causes
of CDH/CVM. In RNA-seq studies, we identified several CDH-associated genes that are dysregulated in the
E15.5 diaphragms of Gata4flox/flox;Prx1-Cre embryos. These embryos are an ideal model of the sac hernias that
comprise 20% of human CDH cases. In Specific Aim #2, we will combine data from RNA-seq and BioChIP-seq
analyses with the priority scores generated in Aim #1 to identify primary GATA4 target genes whose
dysregulation contribute to the development of sac CDH. We will then determine if alterations in the expression
of these target genes can cause CDH, or can modify the CDH phenotypes of GATA4-deficient mice.
 We have shown that SOX7 deficiency causes septal defects by decreasing endothelial-to-mesenchymal
transition (EMT) in the developing heart. In RNA-seq and in situ hybridization studies we have shown that the
expression of Wnt4—a key regulator of EMT in the endocardium—is severely decreased in E9.5 Sox7-/- hearts.
In Specific Aim #3 we will determine if Wnt4 is a primary target of SOX7, and whether modulation of WNT4 or
its downstream effectors can rescue SOX7-related cardiac phenotypes.
 Several lines of evidence suggset that WNT4 is a novel CDH/CVM gene in humans. To confirm this
association, and learn more about the role of WNT4 in diaphragm and heart development, we will determine if
WNT4 deficiency causes CDH/CVM in mice, if Sox7 and Wnt4 interact genetically in the development of
CDH/CVM and if SOX7 regulates Wnt4 transcripition in the developing diaphragm.
 Through these studies we will identify novel CDH and CDH/CVM genes and pathways. The bioinformatic
tools we develop in this grant wil...

## Key facts

- **NIH application ID:** 10201699
- **Project number:** 5R01HD098458-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Daryl Armstrong Scott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $448,377
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201699

## Citation

> US National Institutes of Health, RePORTER application 10201699, Mechanisms of Abnormal Diaphragm and Cardiac Development (5R01HD098458-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10201699. Licensed CC0.

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