AI-MARRVEL and Genomics Uncover BRSK1 Gene Behind Rare Neurodevelopmental Disorder in 10 Patients

AI-MARRVEL Breaks Diagnostic Deadlock in Rare Neurodevelopmental Disorder

Researchers at Baylor College of Medicine, the Duncan Neurological Research Institute at Texas Children's Hospital, and the Texome Project have identified variants in the BRSK1 gene as the underlying cause of a complex neurodevelopmental disorder that had left families without answers for years1

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. The breakthrough came through genomics and AI, specifically an artificial intelligence tool called AI-MARRVEL, which analyzed genomic data when standard genetic testing failed to provide a diagnosis. Published in the American Journal of Human Genetics, the study examined 10 affected individuals from seven unrelated families, all carrying rare variants in the same candidate gene1

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The investigation began with a child enrolled in the Texome Project, a program offering free genetic testing for medically underserved individuals with rare, undiagnosed conditions. Standard parent-child genetic analyses yielded no clear answer, but AI-MARRVEL highlighted a rare change in the BRSK1 gene as a promising candidate for a genetic diagnosis1

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. Dr. Hugo Bellen, co-lead author and Distinguished Service Professor at Baylor College of Medicine, explained that after sharing this finding through GeneMatcher, a research network connecting geneticists evaluating identical genes, additional families reported rare variants in the same gene1

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Variable Clinical Presentation Challenges Diagnosis

All affected individuals showed some degree of developmental delays, but the severity and specific symptoms varied dramatically across the cohort. Common features included delayed speech and language development, intellectual disability, autism spectrum disorder traits, attention-deficit/hyperactivity disorder, anxiety, low muscle tone, and microcephaly—a smaller-than-average head size1

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. Two individuals experienced seizures, adding another layer of complexity to the clinical picture1

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What makes this rare neurodevelopmental disorder particularly challenging is its variable expressivity. Even among members of the same family carrying the identical genetic variant, symptoms ranged from mild learning challenges to severe neurological impairment1

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. This suggests the same genetic change can affect people differently, complicating both diagnosis and prognosis for families navigating this condition.

Fruit Fly Experiments Reveal Pathogenic Role

To determine whether the BRSK1 gene variants in patients disrupt gene function, researchers turned to Drosophila melanogaster, the laboratory fruit fly. The BRSK1 gene produces a protein that helps neurons develop normally, form connections, and communicate with one another through synaptic structure1

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. Previous studies have shown this protein helps organize the internal structure of nerve cells and supports communication at synapses, the junctions where neuronal development occurs1

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Dr. Mingxi Deng, first author and postdoctoral fellow in the Bellen lab, studied the fly equivalent of BRSK1, called sff (sugar-free frosting). The team found this gene is active primarily in neurons, mirroring the expression pattern seen in humans1

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. When the fly gene was disabled, 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 lives1

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Human Gene Variants Show Reduced Protein Activity

When researchers introduced the normal human BRSK1 gene into flies lacking the sff gene, the human gene largely corrected the flies' movement and neurological problems, demonstrating that human and fly genes perform similar roles1

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. However, when they introduced the gene variants found in affected individuals, the neurological and movement problems were only partially restored, suggesting these variants reduce but do not completely eliminate the protein's activity1

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Further fruit fly 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 microtubule organization, a structural framework inside neurons1

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. Microtubule disruption has been linked to several neurodevelopmental and neurological disorders, suggesting that reduced BRSK1 function interferes with the cellular machinery needed for healthy brain development and communication between neurons1

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Implications for Genomic Medicine and Rare Disease Diagnosis

Taken 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 epilepsy1

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. This work improves 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 biology1

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For families navigating rare, undiagnosed neurodevelopmental conditions, securing a definitive genetic answer can take years of inconclusive testing2

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. While next-generation exome sequencing has transformed clinical diagnostics, identifying which specific ultra-rare mutation is actively pathogenic remains a formidable bottleneck2

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. The Texome Project addresses the fact that many people do not have access to genomic medicine, providing a pathway for medically underserved populations to receive comprehensive genetic testing1

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. Watch for expanded use of AI tools like AI-MARRVEL in clinical settings as researchers continue decoding the genetic basis of rare conditions that have long evaded diagnosis.