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.
