Recurrent de novo ABI2 p.Tyr491Cys variants define a neurodevelopmental syndrome with corpus callosum hypoplasia and white matter abnormalities

Abstract 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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Journal
The American Journal of Human Genetics
Published
2026-11-01
DOI
https://doi.org/10.1016/j.ajhg.2026.10.003
Citations
1
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
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article

Recurrent de novo ABI2 p.Tyr491Cys variants define a neurodevelopmental syndrome with corpus callosum hypoplasia and white matter abnormalities

Sureni V. Mullegama, Elizabeth George, Alicia B. Byrne, Caleb Yang et al.
1 citations
The American Journal of Human Genetics
Genetics and Neurodevelopmental Disorders
article

Recurrent de novo ABI2 p.Tyr491Cys variants define a neurodevelopmental syndrome with corpus callosum hypoplasia and white matter abnormalities

Sureni V. Mullegama, Elizabeth George, Alicia B. Byrne, Caleb Yang, James J. Dowling, Eleina M. England, Emanuela Argilli, Kimberly Amburgey, Alexis Bosman, É. Rossignol, Erfan Aref‐Eshghi, Michelle M. Morrow, Ruiji Jiang, Jacques L. Michaud, Louisa Kalsner, Deepa Soundara Rajan, Sonal Mahida, Brian G. Skotko, Carolyn Le, Christine Munro, Clare Bakker, Amanda M. Elashoff, Christopher Barnett, Zornitza Stark, Heather Olson, Fadi F. Hamdan, Nancy Pinnell, Elliott H. Sherr, Hanna Retallack, Kendall Parks, Di Milnes
article en
1 citations

Abstract

Abstract 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.

The American Journal of Human Genetics
Broad Institute (US), South Australia Pathology (AU), Boston Children's Hospital (US), University of Pittsburgh (US), University of South Australia (AU), University of California, San Francisco (US), Women's and Children's Hospital (AU), Hospital for Sick Children (CA), Massachusetts General Hospital (US), UPMC Health System (US), Connecticut Children's Medical Center (US), Children's Hospital of Pittsburgh (US), University of Pittsburgh Medical Center (US), Centre for Cancer Biology (AU)
National Institutes of Health, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke
Good health and well-being
Openalex Percentile: Top 100%
Genetics and Neurodevelopmental Disorders
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