Abstract
Asymptomatic individuals with pathogenic variants in OTC, the gene encoding ornithine transcarbamylase are increasingly being identified through cascade testing, carrier screening, or as secondary findings from genome-wide sequencing tests. However, guidance for counseling and management of such individuals is currently lacking. We selected two common OTC variants for phenotypic and functional characterization: NM_000531.6:c.118C>T p.(Arg40Cys) and NM_000531.6:c.1061T>G p.(Phe354Cys). The former is the most frequently reported pathogenic/likely pathogenic missense variant present in gnomAD, and the latter has been frequently encountered in our clinical practice. We performed a retrospective chart review at our center, queried the database of the Urea Cycle Disorders Consortium, and performed a literature review to create cohorts of individuals with these variants. Functional studies were pursued using a validated yeast-based assay. We identified 14 individuals (6 females, 8 males) with the p.(Arg40Cys) variant and 14 individuals (5 females, 9 males) with the p.(Phe354Cys) variant. There were no reported episodes of neonatal hyperammonemia in males and no hyperammonemic events reported in females with either variant. In our functional assay, both variants reduced yeast growth to the hypomorphic range. Our findings support the classification of both p.(Arg40Cys) and p.(Phe354Cys) variants in OTC as hypomorphic variants that are typically associated with late-onset OTCD in males.