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

Previous research in other disorders has indicated that problems 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 a spliceosome. Variants affecting the spliceosome have rarely been linked to neurodevelopmental disorders. However, through a series of complex tests, the researchers in this study demonstrated that dysfunctions in the spliceosome are responsible for some neurodevelopmental disorders.

“Using multiple techniques, including phenotyping, genomic sequencing, and modeling in flies 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 at the Center for Applied Genomics and the Division of Human Genetics at Children’s Hospital of Philadelphia (CHOP) in the United States.

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

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

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

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