Asymptomatic individuals with pathogenic variants in OTC 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 (six females, eight males) with the p.(Arg40Cys) variant and 14 individuals (five females, nine 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. Taken together, 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.

• PMID: 41108081
• DOI full text
• PubMed
• PubTator

Reference Type

Journal Article

Authors

Lang SH, Lo RS, Cromie GA, Dudley AM, Mew NA, Simpson K, Sutton VR, Darilek S, Ali S, Snyder MT, ... Show all

Primary Lit For

Additional Lit For

Review For