Summary:
Using the artificial intelligence tool AI-MARRVEL alongside functional fruit fly models, researchers have identified rare variants in the BRSK1 gene as the underlying cause of an undiagnosed neurodevelopmental condition. The study demonstrates that reduced BRSK1 function disrupts microtubule organization and synaptic structure, triggering developmental delays, speech deficits, autism traits, and variable neurological symptoms.
Key Facts:
- AI-Powered Gene Discovery: The diagnostic breakthrough began through the Texome Project, where standard genetic screens failed, but the machine-learning tool AI-MARRVEL identified a rare variant in BRSK1 that was subsequently matched across 10 individuals in seven unrelated families.
- Variable Clinical Presentation: While all affected individuals exhibited developmental delay, the condition displays high “variable expressivity”, with symptoms ranging from speech delays, intellectual disability, and microcephaly to ADHD, autism spectrum disorder, low muscle tone, and seizures.
- Microtubule and Synaptic Disruption: Functional modeling in Drosophila revealed that patient-derived BRSK1 mutations reduce protein activity, elevate microtubule-organizing proteins, and trigger abnormal structural overgrowth at neuromuscular synapses.
Source: Baylor College of Medicine / Texas Children’s Hospital
For families navigating rare, undiagnosed neurodevelopmental conditions, securing a definitive genetic answer can take years of inconclusive testing. While next-generation exome sequencing has transformed clinical diagnostics, identifying which specific ultra-rare mutation is actively pathogenic remains a formidable bottleneck.
Now, a collaborative team led by researchers at Baylor College of Medicine, the Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, and the Texome Project has identified variants in the BRSK1 gene as the genetic cause of a complex, previously unexplained neurodevelopmental disorder.
The study, published in the American Journal of Human Genetics, showcases how artificial intelligence and classic model organism genetics can join forces to decode the human genome.
From Algorithmic Candidate to Global Cohort
The investigation originated with a pediatric patient enrolled in the Texome Project, an initiative established to provide free, comprehensive genomic testing for medically underserved families across Texas. Standard parent-child trio sequencing initially failed to yield a clear molecular diagnosis.
To break the diagnostic deadlock, researchers deployed AI-MARRVEL, an advanced artificial intelligence tool designed to prioritize pathogenic mutations by integrating multi-omics databases, clinical presentation, and model organism functional data. The algorithm surfaced a rare variant in the BRSK1 gene as a prime candidate.
“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,” said co-lead author Dr. Hugo Bellen, Distinguished Service Professor of Molecular and Human Genetics at Baylor and chair in neurogenetics at the Duncan NRI.
The researchers broadcasted their candidate through GeneMatcher, a global networking database that connects geneticists evaluating identical candidate genes. The international search rapidly expanded the cohort.
“Altogether, we studied 10 affected individuals from seven unrelated families,” said first author Dr. Mingxi Deng, a postdoctoral fellow in the Bellen lab.
High Clinical Variability in BRSK1 Syndrome
Every patient identified across the seven families exhibited some degree of global developmental delay, though clinical severity differed markedly. Common symptoms included:
- Delayed speech and expressive language development
- Intellectual disability
- Autism spectrum disorder traits and anxiety
- Attention-deficit/hyperactivity disorder (ADHD)
- Hypotonia (low muscle tone) and microcephaly (reduced head circumference)
- Seizure disorders (observed in two individuals)
Even among members of the same family sharing the identical genetic mutation, symptom severity diverged from mild learning challenges to profound neurological impairment, demonstrating substantial variable expressivity.
Probing Synaptic Wiring in Fruit Flies
Biochemically, BRSK1 encodes a serine/threonine-protein kinase known to regulate neuronal polarization, synapse formation, and inter-neuronal communication. To definitively prove that the patient variants impaired protein function, the researchers engineered Drosophila melanogaster models.
The investigators targeted the fly homolog of BRSK1, known as sff (sugar-free frosting), which mirrors human BRSK1 by functioning primarily in mature neurons. Disabling sff in flies caused motor dysfunction, shortened lifespans, increased vulnerability to heat-induced paralysis, and pronounced hypersensitivity to seizure-inducing stressors.
Expressing healthy human BRSK1 rescued these locomotor and neurological deficits, proving evolutionary functional conservation. However, introducing the mutated human variants found in patients only partially restored function, confirming that the patient mutations behave as partial loss-of-function (hypomorphic) alleles rather than total knockouts.
Further molecular dissection revealed the cellular mechanism: diminished BRSK1 activity sparked abnormal structural overgrowth at synaptic terminals and elevated levels of proteins that organize microtubules—the structural scaffold of axons and dendrites.
“Microtubule disruption has been linked to several neurodevelopmental and neurological disorders,” Deng explained. “Our findings suggest that reduced BRSK1 function interferes with the cellular machinery needed for healthy brain development and communication between neurons.”
Expanding Genomic Access
The validation of BRSK1 delivers long-awaited diagnostic closure for affected families and adds a new gene to clinical developmental screening panels.
“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.”
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and neurodevelopment Research:
- Media Contact: Graciela Gutierrez
- Source: Baylor College of Medicine
- Image Credit: Image credited to Neuroscience News
- Original Research is Open Access: American Journal of Human Genetics (Sept 22, 2026). “Monoallelic variants in BRSK1 are associated with a neurodevelopmental disorder with or without epilepsy.” Authors: Mingxi Deng, Mengqi Ma, Vanessa Andrea Gomez, The Community Texome, Michael F. Wangler, and Hugo J. Bellen.
- DOI: 10.1016/j.ajhg.2026.09.005
Abstract
Monoallelic variants in BRSK1 are associated with a neurodevelopmental disorder with or without epilepsy
Brain-specific serine/threonine kinase (BRSK1; synapses of amphids defective [SAD]-B) encodes an AMP-activated protein kinase (AMPK)-related serine/threonine kinase required for neuronal polarization and synaptic function.
An individual with a variant in BRSK1 was identified in the Texome Project, which provides genomic diagnosis to financially disadvantaged individuals in Texas, using AI-MARRVEL. We subsequently found nine individuals harboring rare heterozygous BRSK1 variants through GeneMatcher.
Affected individuals present with developmental delay and variable phenotypes including anxiety, attention-deficit hyperactivity disorder (ADHD), autism, and seizures. All variants (missense and nonsense) are predicted to be deleterious by pathogenicity prediction tools. We utilized Drosophila to model three missense variants to assess the impact of the variants in vivo.
We show that Drosophila sff (sugar-free frosting; ortholog of BRSK1) is expressed in neurons of the larval central nervous system (CNS) and adult brain. Loss of sff leads to viable flies with severe locomotor impairment, bang and heat sensitivity, and a short lifespan. In addition, the third-instar neuromuscular junctions (NMJs) in sff null mutants display a significant overgrowth, associated with elevated levels of Futsch (MAP1B), a microtubule-associated protein.
Expression of the human reference BRSK1 cDNA in the sff null mutant rescues the behavioral, NMJ morphology, and Futsch phenotypes, showing that the human gene is functional in flies. In contrast, the three individual-derived alleles (BRSK1p.Ile202Val, BRSK1p.Arg237Cys, and BRSK1p.Thr406Ile) provide only a partial rescue and fail to normalize NMJ morphology and Futsch levels, suggesting that they are partial loss-of-function alleles.
In summary, our data support a model that heterozygous loss of BRSK1 leads to a neurodevelopmental syndrome with variable phenotypes.
