Systematic identification and phenotypic characterization of causal genetic variants in rare disease-associated birth defects

Active Project Grant Awarded Last action

Award ID
R01HD110447
Recipient
Awarding agency
Obligated
$10,050,082

Award facts

Completion date 78% complete
Place of performance
Kansas City, MO 64108, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Although the implementation of whole exome sequencing (WES) and whole genome sequencing (WGS) in a clinical setting has greatly facilitated the identification of birth defect-associated genetic variants, distinguishing the specific variants that cause congenital defects remains a major challenge. More specifically, most variants detected in clinical sequencing occur in genes not previously associated with disease or in noncoding regions of the genome that lack predictable functional consequences. Enhancing the ability to illuminate causal variants holds the promise of improving the quality of life for patients and in some cases may provide a window for therapeutic intervention that would otherwise be missed. In this proposal we leverage our institute's unparalleled pediatric genetic data repository to guide the development of scalable cell-based systems that, when coupled with phenotypic validation in both animal and patient-derived organoid models, will systematically identify genetic variants that are responsible for congenital defects in our undiagnosed rare disease patient population. We will (aim 1) catalog loss-of-function variants associated with the most prevalent congenital defects in our patient population, perform genome-scale crispr screens in relevant organoid models to distinguish variant-harboring genes that play a role in development, and validate the phenotypic consequences of gene loss in a zebrafish model. In parallel, we will (aim 2) catalog noncoding variants (i.e. intronic, putative CIS-regulatory) associated with prevalent congenital defects, develop a suite of massively parallel genomic assays capable of profiling the regulatory impact of noncoding genetic variants at scale, and perturb the expression of candidate variant- associated genes in a zebrafish model to determine the phenotypic consequences. Finally, we will (aim 3) generate patient-derived organoid models, utilize precision genome engineering in combination with single-cell transcriptomics in patient-derived organoids to validate the causal role of specific variants in congenital defects, and characterize the impact of variants on development using spatial transcriptomics in patient-derived organoids as a proxy. We anticipate that the work outlined in this proposal will establish an experimental framework that can be deployed to identify genetic variants that are responsible for a wide variety of congenital defects.

Transactions

Action Obligated Date
Amendment $62,596
Amendment $563,363
Amendment $563,363
Amendment $64,111
Amendment $577,011
Amendment $577,011
Amendment $577,011
Amendment $577,011
Amendment $59,252
Amendment $59,252
Amendment $59,252
Amendment $592,525
Amendment $592,525
Amendment $592,525
Amendment $592,525
Amendment Investigating stakeholder perspectives to inform ethical use of organoids in pediatric rare disease research $245,138
Amendment $245,138
Amendment $245,138
Amendment $641,067
Amendment $641,067
Amendment Investigating stakeholder perspectives to inform ethical use of organoids in pediatric rare disease research $641,067
Amendment $641,067
Original award $641,067
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Subawards

Subrecipient Amount Awarded
Stowers Institute For Medical Research This proposal aims to build a platform that will integrate novel methods and innovative approaches to accelerate the process of translating the clinical… $288,679

Quick answers

Who received award R01HD110447?

R01HD110447 was awarded to Childrens Mercy Hospital by National Institute of Child Health and Human Development (National Institutes of Health) on December 21, 2022.

How much is award R01HD110447 worth?

$10,050,082 has been obligated on R01HD110447.

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