MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families.

Abstract

MAP1B (microtubule-associated protein 1B) encodes a cytoskeletal regulator critical for neuronal migration, axon guidance, and cortical circuit formation. Disease-causing variants (DCVs) in MAP1B have recently emerged as a cause of neurodevelopmental disorders characterized by intellectual disability, epilepsy, and cortical malformations, including periventricular nodular heterotopia (PVNH) and polymicrogyria (PMG). However, the phenotypic and neuroimaging spectrum associated with MAP1B-related disease remains incompletely defined. We describe seven affected individuals from three unrelated families with pathogenic MAP1B variants. Clinical, neuroimaging, and genetic data were analyzed in the context of emerging literature to delineate the pathogenic mechanisms and phenotypic variability associated with MAP1B dysfunction. All individuals carried loss of function MAP1B variants. Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy. Neuroimaging revealed anteriorly predominant PVNH in four of five cases with neuroimaging available. These findings reinforce MAP1B's central role in cytoskeletal regulation, neuronal positioning, and synaptic connectivity. Functional data from animal and cell models support a mechanism involving impaired microtubule stabilization, altered growth cone dynamics, and dysregulated axon branching. Our case series expands the clinical and radiological phenotype associated with MAP1B-related disorders and highlights its position as a key cytoskeletal regulator in human corticogenesis. Systematic genotype-phenotype correlation and functional studies are needed to inform diagnostic interpretation and explore therapeutic avenues in MAP1B-associated disease.