An international team of researchers have identified how three novel genes cause neurodevelopmental disorders, particularly developmental delay, intellectual disability and autism.
Identification of the genes — U2AF2, PRPF19, RBFOX1 — may help researchers gain a better sense of the roles of genes in human brain development and function as well as their ability to serve as potential therapeutic targets in the future.
Prior research in other disorders has shown that issues related to gene splicing may be to blame.
Before being turned into proteins, genes are transcribed into introns, or strands of RNA that do not code for proteins, and exons that code for proteins.
Introns are removed in a process called splicing, which is carried out by a protein complex called the spliceosome. Variants impacting the spliceosome have rarely been implicated with neurodevelopmental disorders.
However, through a series of complex testing, researchers in this study showed 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 noticed 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 loss of proper neuron function.
These findings were later compared with those of patients in the study, which confirmed that variants in the three genes can lead to neurodevelopmental disorders.