Truncating GAS6 Variant Disrupts Neuroglial Homeostasis in a Childhood-Onset Demyelinating Disorder

Growth arrest-specific 6 (GAS6) protein is required for cell survival through its role in TAM receptor signalling. Here, we investigate a novel autosomal recessive demyelinating disorder in a 9-year-old male presenting with progressive motor dysfunction, spasticity, seizures and cognitive decline. MRI revealed multifocal T2/FLAIR hyperintensities in periventricular, juxtacortical and brainstem white matter regions. Exome sequencing uncovered a homozygous stop-gain variant in GAS6 (c.444G>A; p.Trp148Ter). The variant results in nonsense-mediated decay and loss of protein expression and secretion. Functional assays in patient fibroblasts and HOG oligodendrocytes showed downregulation of neurotrophic and myelin-related genes (NTRK2, CNTF, EGR1, MBP, PLP), defective oligodendrocyte-process formation and increased G₀/G₁ cell cycle arrest. Rescue experiments confirmed that wild-type GAS6, but not the truncated variant, restored cellular function. These findings establish GAS6 as a critical regulator of neuro-glial homeostasis and identify its deficiency as the cause of a previously unreported childhood-onset demyelinating disease.