Three genes unravel mysteries behind developmental delay, intellectual disability, and autism

New York: An international team of researchers has identified how three novel genes cause neurodevelopmental disorders, specifically developmental delay, intellectual disability, and autism.

The identification of the genes—U2AF2, PRPF19, RBFOX1—may help researchers gain a better understanding of the roles of genes in human brain development and function, as well as their potential as therapeutic targets in the future.

Previous research in other disorders has indicated that issues related to gene splicing may be responsible. Before being transformed into proteins, genes are transcribed into introns, or strands of RNA that do not code for proteins, and exons that do code for proteins.

In a process called splicing, introns are removed, and this is carried out by a protein complex called the spliceosome. Variants impacting the spliceosome have rarely been linked to neurodevelopmental disorders. However, through a series of complex tests, researchers in this study demonstrated that malfunctions in the spliceosome are responsible for some neurodevelopmental disorders.

"Using multiple techniques, including phenotyping, genomic sequencing, and modelling in fly and stem cells, we were able to map the genetic architecture of three genes associated with neurodevelopmental disorders, particularly developmental delay, intellectual disability, and autism,” said lead author Dong Li, a research faculty member in the Center for Applied Genomics and the Division of Human Genetics at Children’s Hospital of Philadelphia (CHOP) in the US.

"Combining fly and human genetics helped us understand the mechanisms of how variants of these genes affect the machinery of the spliceosome and cause these disorders," Li added.

In the study, published online by the Journal of Clinical Investigation, the researchers utilised genomic and clinical data from unrelated patients with neurodevelopmental disorders. Among the cohort, 46 patients had missense variants of the gene U2AF2, and six patients had variants of the gene PRPF19.

In human stem cell and fly models, the researchers observed issues with the formation of neurites, or protrusions on neurons that give them their shape, as well as issues with splicing and social deficits in the fly models.

Deeper profiling revealed that the third gene, RBFOX1, had missense variants that affected splicing and led to the loss of proper neuron function. These findings were later compared with those of patients in the study, confirming that variants in the three genes can lead to neurodevelopmental disorders.