# Malposed Semilunar Valves in Double Outlet Right Ventricle - A Pilot Genetic Analysis

> **NIH NIH R03** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $82,500

## Abstract

During development, the cardiac outflow tract (OFT) arises primarily from progenitor cells in the so-called
second heart field (SHF) and OFT defects are seen in nearly 30% of all congenital heart disease. Traditionally,
OFT maturation has been modeled as three distinct events – septation, alignment and rotation. Double outlet
right ventricle (DORV) results when the OFT fails to appropriately align itself such that systemic and pulmonary
outflows can exit from the respective ventricles. Although several animal models have been proposed to study
the molecular basis for DORV, these models have failed to sufficiently explain simultaneous alignment and
rotation of the OFT, and as such do not faithfully phenocopy the spectrum of DORV seen in the clinical setting.
Clinically, DORV presents as a spectrum of abnormalities with associated defects in great vessel orientation -
ranging from the tetralogy-type DORV with normally related great arteries (NRGA) to transposition-type DORV
with malposed great arteries (MGA). Surgical management and outcomes are vastly different between these
two types and, hence, studying the underlying unique molecular defects is of intrinsic scientific merit. The
accompanying proposal seeks to utilize genetic mutations identified in children with DORV to inform mutations
seen in a novel mouse model of DORV. The PI has access to clinical and whole exome data from the PCGC of
patients with DORV, which will be analyzed to identify genotype-phenotype correlation with DORV/NRGA vs.
MGA. The PI's lab has established a unique mouse model of DORV, wherein Isl-Cre driven DLL4f/wt mice
exhibit DORV/NRGA, whereas the addition of partial knockout of FGF8 results in DORV/MGA. This system
provides the opportunity to utilize a polygenic inheritance pattern to model clinically relevant DORV phenotypic
variants. RNA-seq analysis from these two lesion sets will be used to identify murine mutations. Superimposing
human and murine data will pave way for the understanding of relevant pathways for subsequent analyses.
Given that the PI is a practicing congenital heart surgeon and a cardiac developmental biology researcher, a
key strength of this proposal is the utilization of human data to inform the analysis in a novel mouse model.
The conceptual approach is driven by the PI’s clinical expertise in caring for children with DORV, which has
also provided the ability to study genetic mutations stratified by clinical phenotype. The laboratory aspect of
this project naturally builds upon on the PI’s established expertise studying DLL4 signaling in OFT
development, and utilizes a model of DORV set up as part of a K08 grant from NHLBI. In addition, the proposal
enjoys the support of USC’s Institute of Translational Genomics, which has a robust platform to undertake the
kind of genetic analysis proposed in this study. In the spirit of the R03 mechanism, this pilot work seeks to
analyze genetic data from pre-existing clinical exome sequences and from establi...

## Key facts

- **NIH application ID:** 10064589
- **Project number:** 1R03HL154301-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Ram Kumar Subramanyan
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $82,500
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064589

## Citation

> US National Institutes of Health, RePORTER application 10064589, Malposed Semilunar Valves in Double Outlet Right Ventricle - A Pilot Genetic Analysis (1R03HL154301-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10064589. Licensed CC0.

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