# Multiscale functional characterization of genomic variation in human developmental disorders

> **NIH NIH UM1** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $1,920,132

## Abstract

Project Summary/Abstract
 Large-scale studies have identified thousands of genetic variants linked to developmental defects,
together with the regulatory elements harboring these variants and the cell types in which these variants likely
function. This diversity of variants, regulatory elements, and cell types indicates that multiple mechanisms
contribute to developmental defects. One key challenge to our understanding of these mechanisms is that the
molecular, cellular, and functional phenotypes of each variant remain largely uncharacterized. Until these critical
gaps in knowledge are addressed, the underlying molecular and cellular determinants of developmental disease
susceptibility will remain incomplete. To bridge these gaps, we propose to establish the “UT Southwestern
Center for Regulatory Element Variation and Function”. The primary goal of this Center is to systematically
catalog molecular and cellular phenotypes for disease-associated enhancers in human development, with a
focus on gaining insights into mechanisms of non-canonical human genetics and gene regulation.
 To build a generalizable framework to understanding the impact of human genetic variation on function,
we propose a high throughput perturbation platform with three primary goals: (1) Contribute to a
variant/element/phenotype catalog with relevance to diseases of human development, focusing on elements
genetically associated with congenital heart disease (cardiomyocytes), autism (neurons), and placental defects
(trophoblasts); (2) Contribute to a variant/element/phenotype catalog for non-canonical human genetics,
focusing on two understudied topics in human genetics: pleiotropic effects and non-cell autonomous effects; and
(3) Contribute to a variant/element/phenotype catalog with relevance to mechanisms of gene regulation, focusing
on enhancer RNAs. The Center will take advantage of recent technological innovations in genome engineering,
single-cell genomics, and high content screening to enable the multiscale functional characterization of genomic
variation in human developmental disorders. Several of these techniques have been pioneered by investigators
contributing to this project, including: the development of novel tools for enhancer perturbation and the coupling
of endogenous enhancer perturbations with a single-cell RNA-Seq readout (Mosaic-Seq).
 Impact and Significance: The efforts on this project will lead to a number of key outcomes and
deliverables, including (1) greater understanding of the relationships between sequence variation and genome
function, (2) an extensive variant/element/phenotype catalog for the community, (3) tools for generating
predictive models for the community, and (4) resources to enable future functional genomics studies. Together,
our multifaceted and combinatorial approaches will open new horizons to understanding the impact of regulatory
variants on developmental disease phenotypes.

## Key facts

- **NIH application ID:** 10845535
- **Project number:** 5UM1HG011996-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Gary Chung Hon
- **Activity code:** UM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,920,132
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845535

## Citation

> US National Institutes of Health, RePORTER application 10845535, Multiscale functional characterization of genomic variation in human developmental disorders (5UM1HG011996-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10845535. Licensed CC0.

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