Lissencephaly is a neurodevelopmental disorder characterised by a loss of brain folds. More than 30 genes have been implicated in over 80% of lissencephaly cases, but the genetic origins of the remaining cases are yet to be identified. Here, Jin-Wu Tsai and colleagues uncover a new variant associated with lissencephaly in a patient. First, the authors use whole exome sequencing and identify a single nucleotide variant of BAIAP2, which encodes BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), an actin-binding protein. To explore the role of BAIAP2 in brain development, the authors use spatial transcriptomics to find that BAIAP2 is expressed in a gradient along the posterior-anterior axis, with higher expression in the posterior region. This expression pattern correlates with the phenotype observed in the patient — the brain folding defect is more severe in the posterior than in the anterior region. Furthermore, using in utero electroporation in the developing mouse cerebral cortex, the authors find that loss of BAIAP2 leads to abnormal neuronal morphology, migration and differentiation. Finally, the authors observe that the variant reduces the localization of the protein to the cell membrane. Overall, the findings identify BAIAP2 as a previously unreported gene associated with lissencephaly and uncover its role in brain development.
