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A system approach to the analysis of Heterotaxy Candidate Genes

Award Number: R01HD102186
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/23/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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A system approach to the analysis of Heterotaxy Candidate Genes - PROJECT SUMMARY Congenital malformations are the major cause of infant mortality in the US. However, our understanding of the genetic causes of congenital malformations is severely limited negatively impacting our ability to care for these patients. To discover the genetic causes, we and others have employed human genomics analyses on patients. In particular, we have focused on Heterotaxy (Htx), a disorder of left-right patterning. Normally, our internal organs are asymmetrically distributed along the left-right axis and failure of this process can lead to severe disease including congenital heart disease, gut malrotation, and immune deficiencies. Human genetic analysis of these patients has identified many candidate genes, but the functional relevance is unclear since a plausible disease pathogenesis mechanism is unknown for nearly all of the candidate genes. In the previous grant period, we proposed a gain of function screen where we overexpressed Htx candidate genes in Xenopus looking for potent phenotypes. While this strategy has limitations, we discovered multiple genes that gave interesting phenotypes that led to exciting new insights into Wnt and Cilia signaling pathways. Funded by the grant proposal, we also developed new techniques for assaying cilia based extracellular fluid flow and notably CRISPR based F0 gene editing. The development of these new technologies has transformed the strategy that we will employ for gene screening in the subsequent grant period. Importantly, we will use F0 CRISPR based loss of function screening which is rapid, inexpensive, and highly effective. Our “next generation” screen will also include an investigation not only of cardiac looping but additional steps in the LR signaling cascade. Finally, we will investigate patient variants and connect with researchers across the world using GeneMatcher to exploit our high-throughput animal model to test additional patient variants and increase the number of experimentally tested alleles in our system. Finally, in a subsequent Aim, we will place Htx candidate genes into four key pathways critical for LR patterning: Cilia, Wnt, Notch, and TGF-β signaling. We have considerable experience in each of these pathways converting novel unexplored genes into molecular mechanisms in each of these pathways. Therefore, our previous experience demonstrates that we are especially well suited to translate patient driven gene discovery into molecular mechanisms.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$5,871 )
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	5	6/4/2025	NON-COMPETING CONTINUATION	-$5,871
														Subtotal = -$5,871

Issue Date FY: 2024 ( Subtotal = $611,071 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	5	5/23/2024	NON-COMPETING CONTINUATION	$55,552
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	5	1/18/2024	NON-COMPETING CONTINUATION	$555,519
														Subtotal = $611,071

Issue Date FY: 2023 ( Subtotal = $617,242 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	4	1/26/2023	NON-COMPETING CONTINUATION	$617,242
														Subtotal = $617,242

Issue Date FY: 2022 ( Subtotal = $617,242 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	3	4/27/2022	NON-COMPETING CONTINUATION	$61,725
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	3	1/31/2022	NON-COMPETING CONTINUATION	$555,517
														Subtotal = $617,242

Issue Date FY: 2021 ( Subtotal = $617,242 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	2	2/25/2021	NON-COMPETING CONTINUATION	$617,242
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	2	4/2/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $617,242

Issue Date FY: 2020 ( Subtotal = $646,936 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	4/23/2020	NEW	$646,936
														Subtotal = $646,936

Grand Total All Awards = $3,103,862

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A system approach to the analysis of Heterotaxy Candidate Genes

Award Number: R01HD102186

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/23/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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