Cognition
Kabuki's Distinct Cognitive Fingerprint
A carefully controlled study reveals that visuospatial weakness — not general intellectual disability — defines the Kabuki thinking profile.
Do people with Kabuki have a specific pattern of cognitive strengths and weaknesses?
Yes. This study compared 22 people with molecularly confirmed Kabuki to 22 others with similar age and IQ. Both groups had intellectual disability, but the Kabuki group scored significantly lower on tasks involving visuospatial perception and visual memory. Importantly, their language skills were at least as good as the controls'.
So it's not just general intellectual disability?
Exactly. Because controls were matched on IQ, the visuospatial weakness can't be explained by lower intelligence alone — it's specific to Kabuki. There was also no difference on a pure motor speed task, so it's not just a problem with hand coordination either.
Why does this matter biologically?
A mouse model of Kabuki showed deficits in the dentate gyrus — a part of the hippocampus critical for spatial memory and the birth of new neurons. The visuospatial weaknesses found in humans with Kabuki line up with what you'd predict from those mouse findings.
Could this help with future treatments?
In mice, the memory and brain-growth deficits were reversed by a drug that keeps genes more active. The visuospatial tests used in this study could serve as outcome measures in future clinical trials of such treatments in humans.
If you've ever had a nagging sense that your child with Kabuki syndrome has a particular kind of difficulty with learning — not just "across the board" — a new study confirms you may be right. And it offers clues about where in the brain those difficulties originate.
Researchers at Johns Hopkins recruited 22 individuals with molecularly confirmed Kabuki syndrome and gave them a carefully chosen set of thinking and memory tests. Then they compared the results — not to the general population, but to 22 other individuals with intellectual disability matched for age and IQ.
What they found was striking. The Kabuki group struggled significantly more with tasks involving visual-spatial skills — seeing, copying, and remembering shapes and designs — even though both groups had similar overall IQ scores.
Why IQ-matched controls matter
This point about matching is worth pausing on. Earlier studies had noted that people with Kabuki seem to have a harder time with visual-spatial tasks.
By comparing the Kabuki group to others with similar overall IQ scores, this study could isolate what's different about the Kabuki cognitive profile specifically. And the answer is clear: the visuospatial difficulty is not just a byproduct of lower IQ. It is something particular to Kabuki.
What exactly was tested
The testing battery was designed to take under two hours and to work across a range of ages. It included tasks like copying a complex figure, recalling that figure from memory after a delay, assembling block designs, and identifying visual patterns. It also included language comprehension, motor speed, and general reasoning tasks.
On every visuospatial and visual-motor measure, the Kabuki group scored significantly lower than the IQ-matched controls. The largest gaps appeared in tasks requiring participants to recall a complex figure from memory — both immediately and after a delay. Copying the figure was also much harder for the Kabuki group.
Meanwhile, there was no significant difference between the groups in general cognition, executive functioning, or motor speed. The fact that pure motor ability was similar in both groups is important: it suggests the Kabuki group's difficulty isn't about hand coordination. It's about processing visual and spatial information.
A hint of strength in language
Interestingly, the Kabuki group scored higher than their matched controls on a sentence comprehension task, though this difference just missed the threshold for statistical significance. The researchers note that this near-finding might partly reflect how the matching was done: because people with Kabuki tend to have a specific drag on visuospatial scores, their overall IQ may underrepresent their verbal abilities. In other words, when you match on full-scale IQ, Kabuki individuals may actually have somewhat stronger language skills than their match suggests.
This pattern — weaker visuospatial skills with relatively preserved language — has been noted in earlier, smaller studies of Kabuki. One longitudinal case study even found that the gap between verbal strengths and visuospatial weaknesses grew wider over time.
What's going on in the brain?
Here is where the study connects human cognition to earlier laboratory findings. Work in a mouse model of Kabuki syndrome — mice carrying a disrupted version of KMT2D, the gene most commonly affected in Kabuki — had already shown specific problems with spatial memory tasks. Those same mice had reduced production of new brain cells in a structure called the dentate gyrus, a small but critical region of the hippocampus involved in spatial learning and memory. They also had a thinner layer of cells in that region.
The dentate gyrus has been specifically linked to spatial pattern separation — the ability to tell apart similar visual scenes or spatial layouts. Tests of visuospatial reasoning and memory are thought to at least partly depend on this brain region.
The human findings in this study closely mirror what the mouse model predicted. The researchers argue that this strongly supports the idea that the hippocampus, and specifically the dentate gyrus, plays a role in the intellectual disability seen in Kabuki.
Why this matters for treatment
In the same mouse model, the cognitive and brain-cell deficits were reversed by postnatal treatment with a type of drug called a histone deacetylase inhibitor. That earlier finding raised the tantalizing possibility that targeted treatments could one day help. But to test such treatments in people, researchers need a reliable, repeatable way to measure whether a treatment is working.
This study begins to provide exactly that. The visuospatial tests that showed the biggest differences between Kabuki individuals and controls — particularly the figure-recall tasks — could serve as outcome measures in future clinical trials. With the focused testing battery described here, the authors say they are laying the groundwork for trials of mechanism-based treatments.
A few caveats
The study mainly represents Kabuki type 1 — caused by changes in KMT2D — since Kabuki type 2, caused by changes in KDM6A, is rarer, and affected boys in particular tend to be too severely affected to complete neuropsychological testing. Twenty of the 22 Kabuki participants carried KMT2D variants.
There was also a notable gender imbalance: 19 of 22 Kabuki participants were female, while the control group was evenly split. The researchers acknowledge this could theoretically act as a confounding factor, though they see no particular reason to think it does.
Too few participants had missense changes — a milder type of genetic variant — to draw conclusions about whether the cognitive profile differs by mutation type, though the researchers' impression is that missense changes may be associated with milder features.
The bigger picture
Kabuki syndrome is one of a growing number of conditions caused by disruptions to the cell's epigenetic machinery — the system that controls which genes are turned on or off. KMT2D helps activate genes by chemically marking the proteins that DNA is wrapped around. KDM6A does something complementary: it removes chemical marks that keep genes silent. Together, these two genes account for roughly a quarter to over half of clinically identified Kabuki cases.
The cognitive profile seen here — strong language, weak visuospatial skills — is strikingly similar to what's seen in Williams syndrome, a very different genetic condition. The two syndromes also share features like relative social strengths and anxiety. The authors speculate this overlap may hint at a deeper biological connection — perhaps the genes behind Williams syndrome depend on the same molecular partners that are disrupted in Kabuki.
Among the many forms of intellectual disability, it is becoming clear that different conditions produce different patterns of strengths and weaknesses. Understanding these patterns doesn't just help with diagnosis. It points researchers toward specific brain regions and biological pathways — and, ultimately, toward the possibility of treatments tailored to each condition.
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