Functional map of 2,193 ASS1 variants offers new detail on citrullinaemia type I severity
A PLOS Genetics study from researchers at Children's National Hospital and the Stowers Institute provides the largest functional dataset to date for variants in ASS1, the gene disrupted in citrullinaemia type I, and reveals unexpected epistatic interactions between variants.
Citrullinaemia type I (CTLN1) is a rare autosomal recessive urea cycle disorder caused by loss-of-function variants in ASS1, which encodes argininosuccinate synthetase (ASS). Reduced ASS enzyme activity impairs the conversion of citrulline to argininosuccinate, causing citrulline and ammonia to accumulate. Clinical severity ranges from severe neonatal hyperammonaemia to mild or asymptomatic adult presentations, and predicting disease course from genotype alone has been difficult.
Russell S. Lo, Gareth A. Cromie, Michelle Tang, Amy Sirr, Ljubica Caldovic, Hiroki Morizono, Nicholas Ah Mew, Andrea Gropman, and Aimée M. Dudley — working across Children's National Hospital, the George Washington University School of Medicine, and the Stowers Institute for Medical Research — report the functional profiling of 2,193 ASS1 missense variants, published in PLOS Genetics on 17 June 2026. Using a yeast complementation system, the team systematically measured the effect of each variant on ASS function, generating one of the largest single-gene functional variant datasets produced to date.
Beyond cataloguing individual variant effects, the study characterises epistatic interactions — cases where the combined effect of two variants differs from the sum of their individual effects. Such intramolecular epistasis has implications for interpreting compound heterozygous genotypes in patients with CTLN1.
The dataset provides a reference that may assist researchers and genetic counsellors engaged in variant classification for ASS1, and is relevant to ongoing efforts to apply deep mutational scanning approaches to rare urea cycle disorders. The work is peer-reviewed and published in PLOS Genetics.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
Citrullinaemia type I is a rare inherited metabolic condition caused by changes (variants) in a gene called ASS1. This gene carries instructions for an enzyme that helps the body process nitrogen, and when the enzyme does not work properly, toxic levels of ammonia can build up — especially in newborns.
Researchers at Children's National Hospital and other institutions in the United States have now systematically tested more than 2,000 different possible changes in the ASS1 gene to measure how each one affects enzyme function. The study, published in the journal PLOS Genetics, also found that combinations of variants can interact with each other in ways that are not easy to predict from looking at each variant alone.
This kind of large-scale functional data may help scientists and genetic counsellors better understand which ASS1 variants are likely to cause disease and how severe symptoms might be — though no change to clinical practice follows directly from a single research study. Researchers say the dataset could be a useful reference for future work on this rare condition.
This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
Sources
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Primary source PLOS Genetics · 2026-06-17Functional profiling of 2,193 ASS1 missense variants: Insights into variant pathogenicity and epistatic interactions in citrullinemia type I