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Large scale genome sequencing and integrative analyses to define genomic predictors of recurrent pregnancy loss

Award Number: R01HD105267
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: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Large scale genome sequencing and integrative analyses to define genomic predictors of recurrent pregnancy loss - SUMMARY: Recurrent pregnancy loss (RPL) occurs in approximately 5% of clinically recognized pregnancy losses. The etiology of RPL is not well characterized: after excluding the known etiologies, approximately half of women with RPL still have no identifiable cause. The fact that RPL is, in fact, recurrent suggests a strong genetic component, however there is currently a very limited understanding of the genomic contributions to RPL. Previous studies are typically deficient in their design, limited by small sample size, incomplete clinical phenotyping and/or the recruitment of singletons only. In this proposal, we put forward our plan to recruit 1000 rigorously-phenotyped RPL trios including from diverse and underrepresented backgrounds across the US and to apply WGS and sophisticated variant detection and interpretation methods developed by our labs to identify pathogenic and likely pathogenic variants for RPL. We will then perform comprehensive integrative data analyses to define the genetic basis of unexplained RPL and map the genes and regions of the chromosome that are absolutely required for human development and a successful pregnancy. Our variant interpretation pipeline includes cutting edge approaches to map likely pathogenic noncoding and structural variants rarely assessed in any pregnancy loss study. We will also perform a pilot RNA-seq study to assess the utility of this approach for gene discovery in the pregnancy loss setting. We will first look for recessive pathogenic variation, including compound heterozygosity and then test for models for de novo mosaicism, mitochondrial mutations, regulatory noncoding variation and overall mutational burden. From these combined analyses, we expect to uncover many variants in genes and regions of the chromosome that are intolerable to functional variation, which we define as the human intolerome. We will build on our previous studies to map the intolerome by combining i) available data from all clinical studies to define the genetic etiology of unexplained pregnancy loss, including data generated in this proposal and in our prior work, ii) network-based approaches to prioritize variants genes important for human development and pregnancy, iii) mouse (KOMP, DMDD/MGI) and cell line knockout studies iv) rare and common disease sequencing studies including Centers for Mendelian Genomics (CMG), Center for Common Disease Genomics (CCDG) and Pediatric Cardiac Genomics Consortium (PCGC), iv) emerging human pangenome studies HPP, and v) population-scale biobank projects such as UK BioBank and All of Us. We will then confirm these predictions via collaborator-led functional studies and retrospective analyses of RPL first losses, siblings and grandparents. The sharing of early, unpublished data from the Yale CMG and HPP enabled by our leadership in these projects is a significant strength of what will be by far the largest and most comprehensive study of RPL performed to date. Our findings will take great strides towards the goal of comprehensively mapping the human intolerome and will further expand and refine the exploratory space in which to investigate the genes and chromosomal regions essential for human development.


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 = $1,479,388 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	4	5/14/2025	NON-COMPETING CONTINUATION	$147,938
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	4	11/7/2024	NON-COMPETING CONTINUATION	$1,331,450
														Subtotal = $1,479,388

Issue Date FY: 2024 ( Subtotal = $1,479,765 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	3	5/2/2024	NON-COMPETING CONTINUATION	$134,524
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	3	12/7/2023	NON-COMPETING CONTINUATION	$1,345,241
														Subtotal = $1,479,765

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	2	6/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $1,509,604 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	2	4/22/2022	NON-COMPETING CONTINUATION	$1,509,604
2022	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	11/10/2021	NEW	$0
														Subtotal = $1,509,604

Issue Date FY: 2021 ( Subtotal = $1,524,247 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	1	7/20/2021	NEW	$0
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	4/15/2021	NEW	$1,524,247
														Subtotal = $1,524,247

Grand Total All Awards = $5,993,004

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Large scale genome sequencing and integrative analyses to define genomic predictors of recurrent pregnancy loss

Award Number: R01HD105267

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: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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