The Abelson-interactor 2 gene (ABI2) encodes a protein that functions as a regulator of Rac-dependent actin cytoskeleton dynamics, a highly coordinated structural framework essential for maintaining intracellular homeostasis and vital in processes such as cell adhesion, communication, membrane transport, migration, cell growth, and development. As a component of the Rac-1 activated WAVE regulatory complex (WRC), ABI2 initiates the actin polymerization machinery Arp2/3 to drive lamellipodia formation, and underlying key cellular processes such as axonal guidance, cell motility, and cell adhesion. Additionally, ABI2 acts as a substrate for non-receptor tyrosine kinases ABL1 and ABL2, with downstream effects controlling neuronal differentiation and migration involved in neocortical development. Here, through exome sequencing and international collaborations, we identify eight unrelated individuals with severe neurodevelopmental delays linked to heterozygous ABI2 missense variants, including a recurrent p.Tyr491Cys in the highly conserved SH3 domain in six individuals. These variants arose de novo in cases where parental testing was available, and were associated with moderate to severe motor delay, absent or delayed expressive language, intellectual disability, seizures, autistic traits, as well as macrocephaly, thinning of the corpus callosum, and remarkable white matter signal abnormalities. This report adds ABI2 to the list of genes implicated in neurodevelopmental disorders, with an additional focus on epilepsy and brain malformations.

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This work was funded by NIH grant R01NS058721. Sequencing and analysis of Individuals 1 and 5 were provided by the Broad Center for Mendelian Genomics, funded by the National Human Genome Research Institute grants UM1HG008900, U01HG0011755, and R01HG009141.

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IRB of University of California, San Francisco gave ethical approval for this work

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