Phenotypic and transcriptomic characterization of biallelic RNU2-2 developmental and epileptic encephalopathy

RNU2-2

Ultra-rare biallelic variants clustering in the conserved 5' domains of the small nuclear RNA RNU2-2, causing aberrant splicing detectable in fibroblasts

The authors screened individuals who underwent whole genome sequencing at the Genomic Medicine Centre Karolinska for Rare Diseases for biallelic RNU2-2 variants. Fourteen individuals from nine families carried twelve ultra-rare biallelic variants clustering in the conserved 5' domains, with genotype data for thirteen of them already reported as part of a larger cohort. All presented with a highly concordant, severe developmental and epileptic encephalopathy: severe to profound intellectual disability, inability to walk or communicate, hyperkinesia and refractory seizures, with infantile spasms and tonic seizures predominating and a Lennox-Gastaut-like picture common. Their phenotypic signature was significantly more similar than that of 703 individuals with complex paediatric epilepsies (p = 0.005). RNA sequencing showed aberrant splicing, pronounced in fibroblasts and undetectable in blood.

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

The most directly actionable point is not the gene but the tissue: aberrant splicing is visible in fibroblasts and invisible in blood, which rules out blood RNA validation for these variants and requires a skin biopsy. The strong phenotypic concordance makes the picture recognizable in clinic, which helps prioritize targeted reanalysis of unsolved genomes. The cohort remains largely redundant with the original series, so this is deep characterization rather than independent replication.

Analysis by Dr Thibaut Benquey