Based on the identification of pathogenic de novo missense variants of U2AF2 in patients with neurodevelopmental disorders (NDDs), an international team of researchers gained novel insights into a genetic network of splicing factors influencing brain development and function. The protein encoded by U2AF2 forms an essential subunit of the spliceosome complex. In DNA transcription, genetic information is first copied into a precursor messenger RNA (pre-mRNA). Besides coding regions (exons), pre-mRNA also contains non-coding introns, which must be removed before the mature mRNA molecule can be used as a matrix for protein synthesis. This splicing process requires assembly of a complex machinery of proteins and RNA components, the spliceosome. It is composed of far more than 100 proteins, but so far germline variants in spliceosome genes have only rarely been implicated in neurodevelopmental or neurodegenerative disorders.

The international study, to which also researchers at the Institute of Human Genetics in Göttingen contributed, revealed that the identified U2AF2 variants cause a neurodevelopmental disorder with a phenotype including but not limited to global developmental delay, mild to severe intellectual disability, autism, behavioral disturbances, and shared facial features. Further investigations including transcriptomics and functional analyses in cells and in fruit fly models support an important role played by U2AF2 in neurogenesis and neurite growth. Additionally, the researchers also detected variants in two further splicing factors, PRPF19 and RBFOX1, that were associated with overlapping NDD phenotypes.

The results of the study have been published in the prestigious Journal of Clinical Investigation.