Researchers and physicians constantly search for novel disease genes that can allow them to figure out why medical problems are not diagnosed in patients.
Researchers identified the BICRA gene's involvement in neural development. Image Credit: Baylor College of Medicine.
The initial clues usually come from genetic testing that shows a mutation or change in a gene, which they observed in a child but not in their parents. This is precisely what led to a new research work recently published in the American Journal of Human Genetics.
A multidisciplinary team, which involved scientists from Baylor College of Medicine, Dana-Farber Cancer Institute, and other institutions, discovered that the BICRA gene is a novel disease gene that plays a key role in a neurodevelopmental disorder and they found proof that this gene functions in neural development in both flies and humans.
These latest findings give answers to families and allow researchers and physicians to gain a better understanding of the workings of the BICRA gene, enabling the development of individualized medical strategies for patients in the days to come.
BICRA mutations are associated with human neurodevelopmental disorders
The first patient identified by the team presented with undiagnosed neurological defects, such as neurodevelopmental delay and other traits that were similar, but not identical, to those seen in patients suffering from Coffin-Siris syndrome. According to genetic studies, the patient carried a mutation in the BICRA gene.
With the help of the online gene-matching tool GeneMatcher, the researchers found 11 more patients with similar conditions carrying BICRA gene variants.”
Dr Hugo Bellen, Study Co-Corresponding Author and Distinguished Service Professor of Molecular and Human Genetics, Baylor College of Medicine
Dr Bellen is also a member of the Jan and Dan Neurological Research Institute at Texas Children’s Hospital.
In all the 12 cases examined by the researchers, mutations in the BICRA gene were new in the patients and not inherited from their parents. A few mutations resulted in the loss of function of the BICRA protein.
Further analyses showed that BICRA mutations can cause disease in a dominant fashion – a mutation of only one of the two copies of the BICRA gene in the genome is sufficient to cause disease.”
Dr Scott Barish, Study Co-First Author Baylor College of Medicine
Dr Barish is a postdoctoral associate in Bellen’s laboratory. The study was carried out in association with the laboratory of Dr Cigall Kadoch at Dana-Farber Cancer Institute and Harvard Medical School.
Zebrafish and fruit flies connect BICRA to neural development
The team focused on fruit flies and zebrafish to analyze the potential link between the BICRA gene and the traits seen in the patients.
We conducted the work with zebrafish in collaboration with the Undiagnosed Diseases Network Zebrafish Core run by Dr. Monte Westerfield and Dr. John Postethwait at the University of Oregon. They made a mutation in the zebrafish version of BICRA that mimicked the mutation in one of the patients. The zebrafish carrying the mutation showed a craniofacial defect that was similar to the facial features observed in the patients.”
Dr Scott Barish, Study Co-First Author, Baylor College of Medicine
Dr Bellen, who is also an investigator at the Howard Hughes Medical Institute at Baylor College of Medicine, added, “In fruit flies, we showed that BICRA is expressed in the nuclei of neurons and glia, both in the larval and adult brain.”
“Identifying BICRA as a disease gene may increase the speed at which other disease genes are identified,” concluded Dr Daryl Scott, the study’s co-corresponding author and associate professor of molecular and human genetics at Baylor College of Medicine
Barish, S., et al. (2020) BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms. American Journal of Human Genetics. doi.org/10.1016/j.ajhg.2020.11.003.