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

Active Project Grant Awarded Last action

Award ID
R01HD114863
Recipient
Awarding agency
Obligated
$4,669,987

Award facts

Completion date 52% complete
Place of performance
Seattle, WA 98122, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $767,869
Amendment $77,585
Amendment $698,255
Amendment $698,255
Amendment $809,341
Amendment $809,341
Original award $809,341

Subawards

Subrecipient Amount Awarded
ST Jude Children's Research Hospital Inc. For scientific contribution, analysis and collaboration on the project via the expertise of Dr Gropman. $41,678
Children's Research Institute Dr. Gropman will be responsible for performing the responsibilities of Co-PI. She will overseeing review of patient data from the UCDC longitudinal study (LS)… $255,617

Quick answers

Who received award R01HD114863?

R01HD114863 was awarded to Pacific Northwest Research Institute by National Institute of Child Health and Human Development (National Institutes of Health) on May 1, 2024.

How much is award R01HD114863 worth?

$4,669,987 has been obligated on R01HD114863.

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