Auditory biomarkers separate Kabuki and Rubinstein-Taybi syndromes from controls
Auditory evoked potentials are emerging as a practical window into how the brain processes sound in Kabuki syndrome and Rubinstein-Taybi syndrome, two rare neurodevelopmental disorders driven by defects in epigenetic machinery. In this preprint, investigators measured cortical responses to passive tonal stimuli and found that the N1-P2-N2 complex differed across affected participants and typically developing controls, with the clearest separation appearing in the mid- to late-phase components. Those findings matter because both syndromes are associated with intellectual disability, yet clinical trials in rare disorders often fail when there is no reliable biomarker to show whether a therapy is moving the nervous system in the right direction.
The biological logic is straightforward. If altered epigenetic regulation changes how cortical circuits mature, then a sound stimulus should not only be processed differently at the bedside or in the lab, but should leave a measurable trace in the timing and amplitude of evoked responses. A biomarker built on that principle could help link molecular correction to functional brain change long before broad cognitive gains become visible.
P2 and N2 carried the strongest group differences
Participants underwent passive listening to monotonal auditory stimuli, and the study focused on the amplitude of the P2, N2, and related components within the N1-P2-N2 sequence. Group differences reached significance for P2, N2, and P2-N2 amplitude. The signal was not uniform across diagnoses: Rubinstein-Taybi syndrome appeared more different from typically developing controls than Kabuki syndrome across these measures.
One sentence captures the core result plainly: the mid- and late-latency auditory response was altered in both syndromes. In practical terms, that means the cortex is not merely hearing the sound; it is encoding it differently at a stage of processing that often reflects higher-order sensory integration rather than the earliest arrival of input.
The pattern also hints at developmental biology rather than peripheral hearing alone. N1 tends to reflect early cortical detection, while P2 and N2 are more tied to later perceptual and cognitive processing. When those later components shift, the most likely interpretation is a change in how cortical networks organize and refine auditory information over time, which is consistent with the neurodevelopmental nature of both conditions.
Language and executive function tracked with evoked response amplitude
The study went beyond group separation and asked whether these electrophysiologic measures aligned with cognition. A standardized cognitive assessment battery was administered, and specific subtests were correlated with AEP values. The strongest relationships emerged in the mid- to late-phase response, especially with language. Across and within the diagnostic groups, P2 amplitude showed a positive correlation with language, while N2 amplitude showed a negative correlation with language.
Those opposing directions are clinically interesting because they suggest the components may be indexing different aspects of cortical maturation or processing efficiency. Larger P2 amplitudes may reflect more robust perceptual or attentional engagement, while more negative N2 amplitudes may mark a distinct stage of cognitive processing that moves in the opposite direction as language skills improve. The exact physiology remains unresolved in this study, but the association is strong enough to justify using these measures as candidate response biomarkers rather than simple descriptive readouts.
A separate relationship appeared between the earlier components and executive function. N1 and P2 correlated more closely with measures of executive functioning than did the later-language associations. This split suggests that the auditory evoked response is not a single monolithic marker. Different components may be capturing different cognitive domains, with early and mid-latency responses reflecting broader control processes and later components mapping more directly onto language-related circuitry.
Why an auditory biomarker could matter in rare-disease trials
The appeal of an AEP biomarker in Kabuki syndrome and Rubinstein-Taybi syndrome lies in its simplicity. It is noninvasive, repeatable, and grounded in cortical physiology that can be measured even in participants who may have difficulty with lengthy behavioral testing. In rare disorders, that matters because cognitive endpoints are often noisy, slow to change, and difficult to power in small cohorts. A biomarker that shifts with treatment could provide a faster bridge between target engagement and clinical outcome.
The rationale is reinforced by preclinical work. Mouse models of both syndromes have shown reversal of cognitive impairment with epigenetic treatments, which makes a neurophysiologic marker especially attractive. If a therapy can normalize cortical processing before it can fully restore language or adaptive function, AEPs may detect that change first. For translational programs, that sequence could reduce uncertainty and help identify whether a candidate treatment is doing more than simply altering a molecular signature.
Still, this is an early biomarker study, not a validation study. Correlation does not guarantee that the signal will behave predictably after treatment, and the directionality of the relationship must be tested in longitudinal cohorts. A biomarker for response needs to change when the brain changes, not only when a subgroup differs from controls at baseline.
A preprint that points to circuit-level readouts, not just diagnosis
The most useful message from this work is not that AEPs differ in two rare syndromes. It is that the auditory cortex may provide a measurable bridge between epigenetic dysfunction and cognition, especially language. The fact that Rubinstein-Taybi syndrome appeared more altered than Kabuki syndrome in group comparisons may eventually help refine syndrome-specific profiles, though the present dataset cannot settle whether that reflects disease severity, developmental timing, or simply sample characteristics.
What remains clinically compelling is the convergence of the physiology and the behavior. Mid- and late-phase auditory responses differed from controls, and those same components related to language and executive function. In a field that urgently needs biomarkers capable of supporting early-phase therapeutic trials, that combination is more informative than either finding alone.
The next step is obvious: longitudinal testing after intervention, with careful assessment of whether AEP shifts parallel meaningful cognitive change. Without that, the field still has a candidate marker rather than a validated one. With it, auditory evoked potentials could become one of the few scalable tools for tracking brain-based treatment response in these epigenetic neurodevelopmental disorders.