article · Epilepsia
Biallelic variants in the RNU2-2 gene cause a severe, recessive form of developmental and epileptic encephalopathy. Examination of 14 affected individuals from nine families revealed twelve ultra-rare variants clustering in conserved five-prime domains. Detailed clinical phenotyping showed a consistent disease profile, characterised by profound intellectual disability, absence of speech and walking ability, hyperkinesia, and treatment-resistant seizures such as infantile spasms and tonic seizures resembling Lennox-Gastaut syndrome. Comparative phenotypic scoring confirmed that this cohort shares a distinct clinical signature distinct from other complex paediatric epilepsies. Transcriptomic analysis demonstrated that these variants disrupt normal cellular function through aberrant RNA splicing. These splicing defects, specifically mutually exclusive exon usage and alternate three-prime splice sites, are pronounced in skin fibroblast tissues but undetectable in blood samples, highlighting fibroblasts as a necessary tissue for functional validation.
Many children with suspected genetic developmental and epileptic encephalopathies remain undiagnosed despite whole-genome sequencing. Pinpointing biallelic RNU2-2 mutations and their distinct clinical manifestations resolves previously unexplained cases. Furthermore, demonstrating that splicing abnormalities are detectable in skin fibroblasts rather than blood offers diagnostic laboratories a clear tissue-specific route to confirm the functional effects of these rare genetic variants.
This research presents diagnostic relevance for clinical genetics laboratories, paediatric neurology clinics, and diagnostic test developers specialising in rare diseases. The identified variant cluster and fibroblast RNA sequencing approach could be integrated into specialised clinical diagnostic workflows to validate RNU2-2 variants. As an early-stage research finding establishing a disease mechanism and functional assay methodology, practical adoption will require further clinical validation and standardised diagnostic assay development.
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OBJECTIVE: A significant proportion of individuals with suspected genetic developmental and epileptic encephalopathies (DEEs) remain unsolved following whole genome sequencing (WGS). Here we describe biallelic RNU2-2 variants causing a recently reported, severe, recessive DEE. METHODS: We screened individuals who have received WGS analyses at the Genomic Medicine Centre Karolinska for Rare Diseases for biallelic RNU2-2 variants. Deep phenotyping was performed through reviewing entire medical histories and phenotypic traits were transcribed to their corresponding Human Phenotype Ontology (HPO) term. HPO terms were used to generate pairwise phenotypic similarity scores and assess for significantly shared phenotype enrichment in the RNU2-2 sub-cohort. RNA sequencing analyses were performed in fibroblast and blood tissues to compare splicing events between RNU2-2 individuals and two independent control groups. RESULTS: We identified 14 individuals from nine families with 12 ultra-rare biallelic RNU2-2 variants clustering in the conserved 5' domains. Genotype data from 13 of 14 individuals has been reported previously as part of a larger cohort. All individuals presented with a highly concordant, severe DEE, characterized by severe to profound intellectual disability, inability to walk or communicate, hyperkinesia, and refractory seizures. Infantile spasms and tonic seizures were the predominant seizure types and a Lennox-Gastaut syndrome-like phenotype was common. These individuals had a significantly similar phenotypic signature when compared with 703 individuals with complex pediatric epilepsies (two-sided Monte Carlo permutation test, p = .005). RNA sequencing analyses showed aberrant splicing, with the most pronounced effects in fibroblast tissues in mutually exclusive exon and alternate 3' splice-site events, which were not detectable in blood. SIGNIFICANCE: We present deep phenotyping data and transcriptomic analyses that provide support for rare, 5' clustering biallelic RNU2-2 variants causing this novel, severe DEE. We propose an RNA sequencing methodology on fibroblast tissue for future validation of RNU2-2 variants.
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DOI: 10.1002/epi.70473
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