Summary:
Researchers using the artificial intelligence tool AI-MARRVEL together with functional fruit fly models have identified rare variants in the BRSK1 gene as the cause of a previously undiagnosed neurodevelopmental disorder. The study shows that reduced BRSK1 function disrupts microtubule organization and alters synaptic structure, producing developmental delays, speech and language deficits, autism traits, and a spectrum of neurological symptoms.
Key Facts:
- AI-driven discovery: The diagnostic lead originated in the Texome Project when routine genetic screens were inconclusive. The AI prioritization tool AI-MARRVEL highlighted a rare BRSK1 variant, which was then matched across 10 affected individuals from seven unrelated families.
- Variable clinical presentation: Although all individuals shared global developmental delay, the condition shows pronounced variable expressivity, with presentations ranging from mild speech delay to intellectual disability, microcephaly, ADHD, autism spectrum traits, hypotonia, and seizures.
- Microtubule and synapse dysfunction: Functional studies in Drosophila demonstrated that patient-derived BRSK1 variants reduce kinase activity, increase levels of microtubule-organizing proteins, and cause abnormal overgrowth at neuromuscular synapses.
Source: Baylor College of Medicine / Texas Children’s Hospital
For families facing rare, undiagnosed neurodevelopmental conditions, reaching a definitive genetic diagnosis can require years of testing and uncertainty. Next-generation exome sequencing has greatly improved diagnostic reach, but distinguishing which ultra-rare variants are truly pathogenic remains a major challenge.
A collaborative team led by investigators at Baylor College of Medicine, the Duncan Neurological Research Institute at Texas Children’s Hospital, and the Texome Project combined AI-based variant prioritization with classic model-organism genetics to identify monoallelic variants in BRSK1 as the genetic basis of a complex neurodevelopmental syndrome.
Published in the American Journal of Human Genetics, the study illustrates how computational tools and biological validation can work together to decode challenging genetic diagnoses. The research began with a pediatric case from the Texome Project, which provides comprehensive genomic testing for medically underserved families. Trio sequencing did not yield a clear result until AI-MARRVEL analyzed the genome and prioritized a rare change in BRSK1.
Following that computational lead, the team used GeneMatcher to connect with clinicians worldwide and assembled a cohort of 10 affected individuals across seven unrelated families. This international collaboration allowed the researchers to define a shared clinical spectrum and pursue functional testing.
Clinical features and variability
All identified individuals exhibit global developmental delay, but the severity and combination of associated features vary widely. Reported signs include:
- Delayed speech and expressive language development
- Intellectual disability of variable severity
- Autism spectrum traits and anxiety
- Attention-deficit/hyperactivity disorder (ADHD)
- Hypotonia (reduced muscle tone) and microcephaly
- Seizures in a minority of cases
Even among relatives carrying the same genetic change, clinical outcomes ranged from subtle learning difficulties to pronounced neurological impairment, highlighting the syndrome’s variable expressivity and the influence of additional genetic or environmental modifiers.
Functional validation in fruit flies
Biochemically, BRSK1 encodes a brain-specific serine/threonine kinase related to AMPK that contributes to neuronal polarization and synaptic development. To test whether patient variants impair protein function, the team modeled three missense alleles in Drosophila melanogaster.
The fly ortholog, sff (sugar-free frosting), is active in mature neurons. Loss of sff produced viable flies with severe locomotor defects, shortened lifespan, increased sensitivity to heat and mechanical stress, and a propensity for seizure-like phenotypes. At the cellular level, sff null mutants showed striking overgrowth of neuromuscular junctions (NMJs) and elevated levels of the microtubule-associated protein Futsch (MAP1B homolog).
Introducing the human reference BRSK1 cDNA into sff null flies restored normal behavior, NMJ morphology, and Futsch levels, demonstrating evolutionary conservation of function. In contrast, the patient-derived human alleles (BRSK1p.Ile202Val, BRSK1p.Arg237Cys, and BRSK1p.Thr406Ile) only partially rescued the phenotypes, indicating these variants act as hypomorphic (partial loss-of-function) alleles. The molecular data support a model in which reduced BRSK1 activity disrupts microtubule organization and synaptic architecture, impairing neuronal communication and development.
Implications and access to diagnosis
Validating BRSK1 as a disease gene provides diagnostic closure for affected families and supports the inclusion of BRSK1 in clinical developmental disorder gene panels. The work also exemplifies how AI tools like AI-MARRVEL can accelerate diagnosis by prioritizing candidate variants for experimental follow-up.
“The Texome Project was designed to expand access to genomic medicine,” said co-lead author Dr. Michael Wangler. “Coupling that mission with AI-driven interpretation has helped us identify new disease genes and provide answers to families who had been searching for a diagnosis.”
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal article was reviewed in full and additional context was provided by 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 (Open Access): American Journal of Human Genetics (Sept 22, 2026). Title: “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
BRSK1 encodes an AMPK-related serine/threonine kinase required for neuronal polarization and synaptic function. An initial case from the Texome Project was prioritized by AI-MARRVEL and, through GeneMatcher, nine additional individuals with rare heterozygous BRSK1 variants were identified. Affected individuals have developmental delay with variable features including anxiety, ADHD, autism traits, and seizures. In Drosophila, loss of the BRSK1 ortholog sff causes locomotor impairment, stress sensitivity, shortened lifespan, and NMJ overgrowth associated with elevated microtubule-associated protein levels. Human reference BRSK1 rescues these defects, whereas patient-derived alleles provide only partial rescue, supporting a partial loss-of-function mechanism. Collectively, these data support heterozygous loss of BRSK1 as the cause of a variable neurodevelopmental syndrome.