A broad spectrum of human neurological diseases linked to variations in one gene, DHX9

An international team of researchers from the GREGoR Research Center at Baylor College of Medicine, the Chinese University of Hong Kong, the German Mouse Clinic and collaborating institutions have provided a genetic diagnosis to a group of 20 patients with hitherto undiagnosed neurological diseases. The team analyzed the patients’ genes and conducted family studies to detect genetic mutations linked to their condition. The results are displayed in American journal of human genetics.

By analyzing the patients’ genes and conducting family and animal studies, the researchers were able to provide a genetic diagnosis to 20 patients.

Our study began with two patients with markedly different neurological conditions for which they had no diagnosis despite extensive testing. Seeking an answer to explain their condition, patients have joined our working group studying the genetic basis or genomics of rare diseases, said first author Dr. Daniel Calame, instructor in pediatric neurology and developmental neuroscience and part of the GREGoR Research Center at Baylor.

At first we had no reason to believe that these patients shared a genetic diagnosis. It was after analyzing their genome sequencing results that we realized that each had a distinct and unusual variant of the gene DHX9.”

This is the first time this gene has been associated with a human disease. Our findings motivated us to expand our efforts to find more cases, eventually the 20 we came across.

Dr. Daniele Calame
One gene, many neurological disorders

One of the striking aspects of this study is that the conditions of the patients are vastly different. Some patients have more serious developmental disorders, including intellectual disability, seizures, and movement disorders. Other patients have less severe conditions, such as autism with normal IQ, while other patients have milder conditions of normal development but nerve degeneration leading to neuropathy, a condition that typically causes numbness or weakness in adolescence or adulthood, Calame explained.

To begin to understand how the variations in the gene DHX9 can disrupt neurodevelopment in such a variety of ways, researchers have conducted laboratory experiments in which the different DHX9 the variants found in the patients were introduced into the cells and their functions compared to that of the DHX9 variant not associated with a condition.

Dr. Shen Gu

These cellular studies allowed us to distinguish quite clearly the functional alterations in the variants in severe cases from those associated with less severe or milder cases, said co-corresponding author Dr. Shen Gu, assistant professor in the School of Biomedical Sciences at the Chinese University of Hong Kong.

For example, some variants associated with severe neurodevelopmental disorders were not located in the cell nucleus where the normal variant is typically found, but outside the nucleus in the surrounding cytoplasm.

Some DHX9 variations were not localized in the cell nucleus, as expected, but in the surrounding cytoplasm. Image courtesy of the authors/AJHG2023.

Another variant linked to severe neurodevelopmental disorders did not affect DHX9 localization but instead increased DNA double-strand breaks, a process that negatively affects DNA integrity and can disrupt the cell’s normal function, Shen said.

In addition to cellular studies, researchers have explored the effect of deleting the Dhx9 gene in animal models. Without the Dhx9 gene, the animals were less active in new environments and had a reduced sense of hearing, indicating a connection between the gene and neural functions, Shen said.

Our study shows DHX9 it is involved in the regulation of mammalian neurodevelopment and neuronal well-being.

Dr. James R. Lupski

This is an extraordinary story of international collaborative science, the global nature of human genetics research, and the insights that can be gleaned from studying neurological diseases from the perspective of genetic and genomic variation, results made possible by the joining of scientific forces of two of my favorite cities: Hong Kong and Houston, said Dr. James R. Luski, professor of pediatrics and molecular and human genetics at Baylor. Lupski is also a correspondent author of this work and principal investigator at the GREGoR Research Center.

Find a complete list of contributors to this work, their affiliations and their financial support in the publication.

By Ana Mara Rodrguez, Ph.D.

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