Together human genetics, AI and animal studies provide diagnosis for rare, complex neurodevelopmental disorder

HOUSTON (September 28, 2026) – Researchers at the Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, Baylor College of Medicine, the Texome Project and collaborating institutions have identified variants in gene BRSK1 as a likely diagnosis for individuals with a rare and complex neurodevelopmental disorder who until now had not received an explanation for their condition. The study appears in the American Journal of Human Genetics. 

Genomics and AI identify a candidate gene 
“The project began with a child enrolled in the Texome Project, a program that provides free genetic testing for medically underserved individuals with rare, undiagnosed conditions,” said co-lead author Dr. Hugo Bellen, Distinguished Service Professor in the Department of Molecular and Human Genetics at Baylor and chair in neurogenetics at the Duncan NRI. “Standard genetic analyses of a parent and child with the condition did not reveal an answer, but when a new artificial intelligence-based tool called AI-MARRVEL analyzed the genomic data, it highlighted a rare change in the BRSK1 gene as a promising candidate for a genetic diagnosis.”

“After sharing this finding through a research network called GeneMatcher, additional families reported rare variants in the same gene. Altogether, we studied 10 affected individuals from seven unrelated families,” said first author Dr. Mingxi Deng, a postdoctoral fellow in the Bellen lab.

All affected individuals showed some degree of developmental delay, but the severity and specific symptoms varied. Common features included delayed speech and language development, intellectual disability, autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, low muscle tone and microcephaly (a smaller-than-average head size). Two individuals experienced seizures. Even among members of the same family carrying the same genetic variant, symptoms ranged from mild to severe. This suggests that BRSK1-related disease has ‘variable expressivity,’ meaning the same genetic change can affect people differently.

The researchers knew that the BRSK1 gene produces a protein that helps neurons develop normally, form connections and communicate with one another. Previous studies have shown that the protein helps organize the internal structure of nerve cells and supports communication at synapses, the junctions where neurons exchange signals. 

Fruit fly studies connect BRSK1 to the human condition
To determine whether the gene variants in patients disrupt gene function and how, the researchers turned to the laboratory fruit fly, Drosophila melanogaster. Fruit flies share many biological pathways with humans and can be used to rapidly test the effects of human genetic variants on the normal functions of specific genes.

“We studied the fly equivalent of BRSK1, called sff (sugar-free frosting), and found that this gene is active primarily in neurons, mirroring the expression pattern seen in humans,” Deng said. “When the fly gene was disabled, the flies developed difficulties moving, showed increased sensitivity to stressors that can trigger seizure-like behavior, became more vulnerable to heat-induced paralysis and lived shorter lives. These findings indicated that the gene is essential for normal nervous system function.”

When the researchers introduced the normal human BRSK1 gene into flies that lack the sff gene, the human gene largely corrected the flies’ movement and neurological problems, demonstrating that the human and fly genes perform similar roles. “However, when we introduced the gene variants found in affected individuals, the neurological and movement problems were only partially restored, suggesting that these variants reduce but do not completely eliminate the protein’s activity,” Deng said. 

Further experiments revealed a possible biological explanation. Loss of BRSK1 activity caused abnormal growth of connections between neurons and muscles and increased levels of a protein involved in organizing microtubules, a structural framework inside neurons. “Microtubule disruption has been linked to several neurodevelopmental and neurological disorders,” Deng said. “Our findings suggest that reduced BRSK1 function interferes with the cellular machinery needed for healthy brain development and communication between neurons.”

Taken all together, the findings provide strong evidence that variants in BRSK1 found in patients cause a disorder characterized by developmental delays and a range of neurological and behavioral symptoms, with or without epilepsy. 

“This work improves our understanding of the genetic causes of neurodevelopmental disorders and highlights the power of combining AI-driven gene discovery with experimental studies in model organisms to uncover new rare diseases and their underlying biology,” Bellen said.

“When we started the Texome Project we wanted to address the fact that many people do not have access to genomic medicine, and we wanted to build a program focused on families in Texas,” said co-lead author Dr. Michael Wangler, associate professor of molecular and human genetics at Baylor and an investigator at the Duncan NRI. “As the project progressed, we learned how artificial intelligence can help us interpret genomic data. Now we also have uncovered new insights into genes such as BRSK1 in neurodevelopmental disease. These discoveries not only help the family, but they ultimately have the potential to benefit many more families in the future.” Learn more about the Texome Project, here.

For the complete list of contributors and financial support for this work, see the publication. 

About Texas Children’s 
Texas Children's, a nonprofit health care organization, is committed to creating a healthier future for children and women throughout the global community by leading in patient care, education and research. Consistently ranked as the best children's hospital in Texas and among the top in the nation, Texas Children's has garnered widespread recognition for its expertise and breakthroughs in pediatric and women's health. The system includes the Texas Children's Duncan NRI; the Feigin Tower for pediatric research; Texas Children's Pavilion for Women, a comprehensive obstetrics/gynecology facility focusing on high-risk births; Texas Children's Hospital West Campus, a community hospital in suburban West Houston; Texas Children's Hospital The Woodlands, the first hospital devoted to children's care for communities north of Houston and Texas Children's Hospital North Austin, the new state-of-the-art facility providing world-class pediatric and maternal care to Austin families. The organization also created Texas Children's Health Plan, the nation's first HMO focused on children; Texas Children's Pediatrics, the largest pediatric primary care network in the country; Texas Children's Urgent Care clinics that specialize in after-hours care tailored specifically for children; and a global health program that is channeling care to children and women all over the world. Texas Children's Hospital is affiliated with Baylor College of Medicine. For more information, visit www.texaschildrens.org.