A deep intronic CPS1 variant causing pseudo-exon activation identified in an adult with molecularly unconfirmed urea cycle disorder.
Miki Honto, Eri Imagawa, Hiroshi Mochizuki et al.
✦ AI-curated · Sources linked
From the abstract
Diagnosing proximal urea cycle disorders (UCDs) remains challenging due to the lack of definitive diagnostic biochemical markers, which can lead to delayed or missed diagnosis. Although molecular genetic testing has improved diagnostic accuracy, some patients still harbor only a single detectable pathogenic variant or no identifiable variants in known disease genes.
Reported results
Targeted gene panel analysis identified a heterozygous CPS1 variant, c.840G>C (p.Val278_Lys280del), inherited from his father. cDNA analysis revealed an aberrant transcript containing a 121-bp pseudo-exon between exons 3 and 4 in CPS1. Subsequent genomic analysis identified a deep intronic variant, c.381+178A>C, located 15 bp upstream of the pseudo-exon acceptor site.
Authors' conclusions
We identified a novel deep intronic CPS1 variant that causes aberrant splicing through pseudo-exon activation. Partial splicing defects associated with this variant may contribute to the relatively mild clinical phenotype, highlighting the importance of transcript-level analyses for achieving accurate molecular diagnosis of UCD.