Functional profiling of 2,193 ASS1 missense variants: Insights into variant pathogenicity and epistatic interactions in citrullinemia type I.
Deep analysis of genetic variants clarifies which DNA changes cause a rare urea cycle disorder, improving diagnosis accuracy.
A comprehensive deep mutational scan of 2,193 ASS1 missense variants (90% of all SNV-accessible substitutions) in yeast provides direct functional evidence enabling reclassification of ClinVar variants of uncertain significance in citrullinemia type I, a urea cycle rare disease. Discovery of intragenic complementation reveals a novel mechanism where deleterious variants from different subunits can partially restore enzyme function, with implications for interpreting compound heterozygotes.
What the study was
- Study design
- High-throughput functional assay (yeast deep mutational scanning)
- Population
- Citrullinemia type I (CTLN1) patients and variant database; 2,193 ASS1 missense variants profiled
- Sample size
- 2193
- Category
- Genomics/Precision Medicine
- Maturity
- Exploratory
- Journal
- PLoS Genet
Why it surfaced
Comprehensive variant atlas for a rare urea cycle disease enabling direct ClinVar VUS reclassification (PS3-level evidence). Conservative score (5/10) applied per non-human study cap despite high translational utility. Intragenic complementation finding is a novel biological discovery with clinical interpretation implications.
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