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Using sequencing, phenotyping, as well as fruit fly and stem cell models, a large international team has identified three genes whose variants were linked to neurodevelopmental disorders, such as developmental delay, intellectual disability, and autism. Each of these genes affects how the spliceosome works. The team suggests this study could lead to new drug targets for such conditions.

“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,” said lead author of the report Dong Li of the Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP).

The study was published this month in The Journal of Clinical Investigation

Over the last twenty years or so, researchers have identified more than 1500 genes in different signaling pathways associated with neurodevelopmental disorders. On average, about one third of patients with neurodevelopmental disorders receive a genetic diagnosis. However, little is known about how these genes are networked and how their malfunction leads to these disorders.

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—strands of RNA that do not code for proteins, and exons that code for proteins. Introns are removed through splicing, which occurs in the spliceosome. Variants impacting the spliceosome have rarely been implicated with neurodevelopmental disorders. However, this team showed that malfunctions in the spliceosome are responsible for some neurodevelopmental disorders.

In this study, researchers utilized 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 a 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.

“We used fruit flies to study the effects of losing the function of these three genes one at a time and found that two genes independently led to brain structural and functional abnormalities, highlighting the essentiality of these genes in development,” said study co-author Yuanquan Song, PhD, an associate professor from the Department of Pathology & Laboratory Medicine at CHOP. “Apart from identifying patients with such variants in these genes for the first time, our extended translational modeling study efforts aimed to determine the underlying functions for these variants further elucidated their clinical relevance.”

“Not only does this study identify three causative genes associated with neurodevelopmental disorders, but it helps us understand how critical pre-mRNA splicing is to the development of the central nervous system,” said senior study author Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP.

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