476: One recurring ABI2 change and a thin brain bridge

[00:00:03] Picture 9 People with no family ties to each other. Each carries a rare change in the same gene, ABI2. [00:00:12] Seven of them carry exactly the same change in the same spot, and in those seven the brain scans showed the same picture. The corpus callosum, the large band of fibers that links the two halves of the brain, was underdeveloped. The two people with other changes in the gene did not show it to how can one small change in one gene leave such a consistent mark? [00:00:38] The question matters because until now the gene had almost no record in human disease. Only two new variants had been reported, both in individuals with autism spectrum disorder and with no further clinical information that was not enough to link the gene to a disease. [00:00:55] Today's study changes that with nine people, one change that keeps coming back, and a shared pattern on the scans of the seven who carry it. [00:01:08] This is base by base. Every episode is built with AI tools from a real Open Access paper curated by a human, and every claim is checked against the paper before we publish. You'll find this episode's fact check score on our website. [00:01:22] Now back to the story. [00:01:29] Today we celebrate the work of Emanuela Argili, Elliot Sher and colleagues from the University of California, San Francisco, and from hospitals and research centers in the United States, Canada and Australia who have advanced our understanding of a rare neurodevelopmental syndrome. This base by base episode is based on their Open Access research letter. Recurrent de novo ABI 2P Tire 491C CIS variants define a neurodevelopmental syndrome with corpus callosum, hypoplasia and white matter abnormalities. Published in the American Journal of human genetics in 2026, The gene ABI2 encodes an adapter protein. It regulates a signaling route called RAC wave and the remodeling of actin, the protein filaments that shape a cell and let it move. [00:02:24] It does this through interactions with ABL family kinases and with the wave regulatory complex, a machine made of five subunits. These pathways are essential for neurite extension, axon guidance and synapse formation. Put another way for nerve cells growing their wires and finding where to connect animal work already pointed at the brain. Experimental studies support a role for ABI2 in building the cortex. In mice, ABI2 deficiency causes impaired neuronal migration, abnormal dendritic spines and corpus callosum abnormalities. But in people, the evidence was thin. Only two de novo missense variants had been reported, both in individuals with autism spectrum disorder. With no additional clinical information available which precluded establishing a gene disease association. [00:03:22] To build the cohort. The team found individuals through exome or genome sequencing and through international data sharing on a platform called genematcher. Clinical data came from medical record review and from questionnaires completed by clinicians. [00:03:37] Brain MRI scans were reviewed centrally. The study was approved by the University of California, San Francisco Review board, and informed consent was obtained from participants. Legal guardians it started with two individuals, both with corpus callosum hypoplasia and the same de novo variant. Geneticists write it P yri491 cis at position 491 of the protein, a tyrosine is replaced by a cysteine. [00:04:07] Then seven more individuals turned up. [00:04:10] Five carried that exact same change. [00:04:12] Two carried different de novo variants at positions 204 and 463. [00:04:18] None of the variants appeared in Nomad version 4.1, a large catalog of human variation, and in seven individuals. Parental testing confirmed the change was de novo absent in both parents. [00:04:35] Where does the recurrent change situation? ABI2 has a Homeobox homology region at one end and an SH3 domain at the other. The SH3 domain mediates its interactions with ABL kinases and the wave complex. The tyrosine at position 491 is a conserved residue inside it. Prediction tools call the change deleterious, with a CAD score of 32 and an MPC score of 1.88. Structural modeling suggests it disrupts the local shape of the domain. The the two other variants lie outside the SH3 domain but were also predicted to be damaging. [00:05:13] Now the people all nine had moderate to severe developmental delay, intellectual disability, or both. [00:05:21] Low muscle tone and motor delay were common with delayed walking and persistent gait problems. [00:05:27] Language was hit hard among individuals older than four years. Most were non verbal or had severely limited expressive language. Three showed developmental regression. Epilepsy occurred in six, typically starting before two years of age, with several seizure types from infantile spasms to absent seizures. [00:05:49] Autism spectrum disorder or autistic features was present in all individuals evaluated beyond early childhood macrocephaly. An unusually large head ranging from 2.5 to 4.2 standard deviations was observed in seven of eight individuals. [00:06:09] Seven of eight, then the scans in all individuals with the recurrent change. Brain MRI showed a highly consistent pattern. All had marked hypoplasia of the corpus callosum. The bridge between the hemispheres was underdeveloped. All had patchy bright spots in the white matter around the ventricles on a scan type called T2 Flair. [00:06:34] Additional findings included a small anterior commissure, which is another bridge between the hemispheres. Mildly reduced white matter volume, mild enlargement of the ventricles with an unusual shape at the front and a persistent cavum septum. Plan pellucidum a small fluid space in the midline. [00:06:55] Two details sharpen the picture. [00:06:58] Myelination, the insulating coat on nerve fibers was normal in all individuals and in two individuals scanned over time. The white matter spots stayed stable or partly improved during childhood. [00:07:11] Now the contrast the two individuals with the other variants did not have corpus callosum abnormalities, reduced white matter volume or ventricle changes. One had mild white matter spots, the other had a normal brain mri. Same gene, different change, different scan. [00:07:29] The authors say this suggests the recurrent variant is associated with a distinct neuroimaging phenotype. [00:07:41] What does it add up to? The Authors conclude that ABI2 is a neurodevelopmental disorder associated gene and that the recurrent change defines a distinctive syndrome developmental delay, epilepsy, macrocephaly, corpus callosum, hypoplasia and white matter changes. [00:07:58] Because it sits in the SH3 domain, a hub for protein interactions, they suggest it disrupts ABI2 dependent signaling. The picture is consistent with disorders caused by disruption of the same same RAC wave pathway, including Those linked to RAC1, CyFIP2, NCKAP1 and WASF1 and ABI2 deficient mice also show corpus callosum abnormalities. [00:08:25] There are limits and they matter. This is a cohort of nine people. The mechanism is inferred from structural modeling and prediction tools, not from experiments with the variant itself itself. [00:08:37] Other clinical features were variable, such as dysmorphic features in four individuals and eye problems in two, and detailed individual level data are available only on reasonable request. [00:08:48] The authors write that future functional studies will be important to explain how ABI2 related disease arises. [00:09:01] So here is where this leaves us 9 unrelated people, 1 gene, 7 share the very same change at position 491 inside the domain that mediates the protein's interactions with its partners and their scans tell the same story, an underdeveloped bridge between the two halves of the brain. [00:09:22] The study expands the spectrum of actin cytoskeleton related neurodevelopmental disorders, and it marks a recurrent hotspot with a consistent, consistent MRI pattern. [00:09:32] What does this mean for the future of families still searching for a name for their diagnosis? [00:09:42] This episode was based on an Open Access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description. If you enjoyed this, follow or subscribe in your podcast app and leave a five star rating. And if you'd like to support our work, use the donation link in the description. Thanks for listening and join us next time as we explore more science base by base.