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Development and application of variant interpretation platforms to advance detection of urea cycle disorders by newborn genome sequencing

Award Number: R01HD114863
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: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Development and application of variant interpretation platforms to advance detection of urea cycle disorders by newborn genome sequencing - Project Summary/ Abstract Urea cycle disorders (UCDs) result from inherited deficiencies in any of the eight proteins that function in the essential biochemical pathway that converts neurotoxic ammonia into urea. Infants with neonatal onset UCDs often appear healthy at birth, but the rapid accumulation of ammonia in their blood and brain can lead to coma and death. Although timely diagnosis and treatment is key to improving patient outcome, the sensitivity, specificity, and variability of the biochemical assays for several UCDs have limited their use in newborn screening. Genome sequencing has the potential to simultaneously screen for most inherited diseases that arise in the newborn period, including many high priority conditions for which reliable newborn screening assays do not currently exist. While UCD screening by newborn genome sequencing (NBSeq) has broad support, variant interpretation is a major obstacle. Specifically, it is not currently possible to make a prognosis when a sequencing report contains one or more uncharacterized variants (variants of uncertain significance, VUS) in a known disease gene. Because each person’s genome contains thousands of rare variants of uncertain significance, NBSeq will frequently return them. We will advance NBSeq for five UCDs (OTC, ASS1, ASL, ARG1, and SLC25A15 deficiencies) through a project that addresses three aspects of this critical unmet need. The first is the paucity of functional data from validated assays that are available for use in variant interpretation. For each of the five genes that underlie these UCDs, we will measure the functional impact of all amino acid substitutions that are likely to occur in the human population. The second is the inability to estimate a patient’s genetic risk of UCDs for alleles of uncertain significance. We will provide clinicians with a tool that allows them to estimate the genetic component of disease severity using functional data. The third is the limited amount of clinical data available for these rare diseases. We will leverage a powerful set of clinical resources, including a large longitudinal study of UCD patients, and a close collaboration between clinicians, technologists, and experts in the biological pathways. Clinical data will inform functional assay design, enable cross-validation of the results with patient phenotypes, and allow us to answer important clinical questions about these rare diseases. Thus, by expanding the early identification of newborns with UCDs, this project will ultimately improve care of infants with these devastating diseases.


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: 2026 ( Subtotal = $767,869 )
2026	2026	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Child Health and Human Development Extramural Research	000	3	3/3/2026	NON-COMPETING CONTINUATION	$767,869
														Subtotal = $767,869

Issue Date FY: 2025 ( Subtotal = $775,840 )
2025	2025	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Child Health and Human Development Extramural Research	001	2	4/22/2025	NON-COMPETING CONTINUATION	$77,585
2025	2025	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Child Health and Human Development Extramural Research	000	2	2/13/2025	NON-COMPETING CONTINUATION	$698,255
														Subtotal = $775,840

Issue Date FY: 2024 ( Subtotal = $809,341 )
2024	2024	PACIFIC NORTHWEST RESEARCH INSTITUTE	720 BROADWAY	SEATTLE	WA	98122	KING	USA	Child Health and Human Development Extramural Research	000	1	4/23/2024	NEW	$809,341
														Subtotal = $809,341

Grand Total All Awards = $2,353,050

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Development and application of variant interpretation platforms to advance detection of urea cycle disorders by newborn genome sequencing

Award Number: R01HD114863

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: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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