human genes

Photo by Sangharsh Lohakare on Unsplash

PHILADELPHIA — Researchers have been able to uncover crucial insights into a child’s brain development. An international team of scientists, led by researchers from the Children’s Hospital of Philadelphia (CHOP), have been able to pinpoint how three novel genes contribute to neurodevelopmental disorders. Their findings not only shed light on these genes’ roles in human brain development but also offer potential therapeutic targets for the future.

Neurodevelopmental disorders encompass a wide range of conditions affecting brain development and function, including developmental delay, intellectual disability, and autism. Over the past two decades, researchers have identified more than 1,500 genes associated with these disorders, yet only about one-third of affected individuals receive a genetic diagnosis. The intricate network of these genes and how their malfunctions lead to these disorders has remained largely unknown.

Previous research in other disorders has suggested that issues related to gene splicing might be a key factor. Before genes are transformed into proteins, they undergo a process called transcription, producing introns (RNA strands that do not code for proteins) and exons (coding regions). The removal of introns, a process known as splicing, is orchestrated by a protein complex called the spliceosome. Variants affecting the spliceosome have seldom been linked to neurodevelopmental disorders. However, through a series of complex experiments, this study demonstrates that malfunctions in the spliceosome play a role in certain neurodevelopmental disorders.

“Using multiple techniques, including phenotyping, genomic sequencing and modeling 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,” says the study’s lead author, Dr. Dong Li, a research faculty member in the Center for Applied Genomics and the Division of Human Genetics at CHOP, in a media release. “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.”

Child brain
(© areebarbar –

In this study, researchers analyzed genomic and clinical data from unrelated patients with neurodevelopmental disorders. Among the cohort, 46 patients had missense variants of the U2AF2 gene, and six patients had variants of the PRPF19 gene. In human stem cell and fly models, researchers observed abnormalities in the formation of neurites (protrusions on neurons that determine their shape), issues with splicing, and social deficits in the fly models. Further examination revealed that a third gene, RBFOX1, had missense variants that impacted splicing and disrupted proper neuron function. Comparison with patient data confirmed that variants in these three genes can indeed 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,” explains study co-author Dr. Yuanquan Song, 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.”

“This study not only identifies three causative genes associated with neurodevelopmental disorders but also underscores the critical role of pre-mRNA splicing in the development of the central nervous system. These findings open new avenues for research and potential treatments in the field of neurodevelopmental disorders,” notes study senior author Dr. Hakon Hakonarson, director of the Center for Applied Genomics at CHOP.

The study is published in the Journal of Clinical Investigation.

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