A deep intronic CPS1 variant causing pseudo-exon activation identified in an adult with molecularly unconfirmed urea cycle disorder.

A deep intronic CPS1 variant activates a 121-bp pseudo-exon, generating an aberrant transcript that causes a partial urea cycle defect.

Diagnosing proximal urea cycle disorders remains difficult in the absence of a specific biochemical marker, and some patients carry only a single detectable pathogenic variant. The authors report a late-onset adult Japanese patient who remained without a molecular diagnosis despite strong clinical suspicion: panel sequencing had found a single heterozygous CPS1 variant, c.840G>C (p.Val278_Lys280del), inherited from his father. Blood-derived cDNA analysis revealed an aberrant transcript containing a 121-bp pseudo-exon between exons 3 and 4, leading to identification of a deep intronic variant, c.381+178A>C, located 15 bp upstream of the pseudo-exon acceptor site. A minigene assay in HEK293T cells confirmed that this variant induces pseudo-exon inclusion, and this partial splicing defect may explain the relatively mild phenotype.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is the now classic missing second allele scenario, and the demonstration is clean, from cDNA to minigene, with no bioinformatic shortcut. The lesson is methodological rather than genetic: in a monoallelic urea cycle disorder, transcript-level analysis should be offered before concluding, something WGS alone does not solve if intronic annotation is not interrogated. It remains a single case, without replication or frequency data, hence a private variant for now.

Analysis by Dr Thibaut Benquey