Media release

From: Springer Nature

1.  Health: Mutations to a non-coding gene associated with intellectual disability *PRESS BRIEFING*

Rare mutations to RNU4-2 — a gene that encodes a critical component of an RNA–protein complex called a spliceosome — may be a contributing factor in a greater proportion of clinically diagnosed intellectual disability cases than any other non-sex-related gene identified so far, reports a large genetic study in Nature Medicine. These newly identified mutations have the potential to inform clinical diagnostic and therapeutic approaches for certain neurodevelopmental disorders.

Intellectual disability (ID) is a neurodevelopmental disorder characterized by difficulties in intellectual functioning, as well as in social and practical skills. Although 1,427 genes are linked to ID, most ID cases remain unexplained after genetic testing. All but 9 of the 1,427 known genes are protein-coding, in part because the largest genetic studies of ID have used whole-exome sequencing, which typically omits non-protein-coding genes. Spliceosomes are molecular machines that remove introns (non-coding sections) from pre-mRNA, joining the remaining exons (coding sections) to form mature mRNA.

Daniel Greene, Ernest Turro and colleagues conducted a genetic association analysis using whole-genome sequencing data from 77,539 participants enrolled in the 100,000 Genomes Project, a large genetic database created to help researchers identify mutations responsible for diseases with unknown causes. The dataset included 5,529 people clinically diagnosed with ID. The authors identified rare new mutations in the non-protein-coding gene RNU4-2 — which encodes a spliceosome component — that were strongly associated with the potential to develop ID. These associations were further validated in three large and independent genetic databases, and the authors identified 73 affected cases across all four collections.

The authors emphasize that the precise mechanism underlying these mutations remains unclear and needs to be investigated in further studies. However, these results provide a potential genetic cause for many clinically diagnosed neurodevelopmental disorders with previously unknown causes.

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