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

ABSTRACT 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 G 0 /G 1 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.