Seizures and Functional Deficits across Mendelian Disorders of Epigenetic Machinery: Differential Effects as a Function of Epigenetic Modifications.

Intellectual disability is common in a large proportion of Mendelian disorders of epigenetic machinery (MDEMs), underscoring the strong association between epigenetic dysregulation with the developmental disorder. However, the epigenetic factors/mechanisms that drive differences in neurodevelopmental presentation and severity remain unclear. This preliminary study aimed to identify neurobehavioral differences across MDEMs involving genes related to chromatin writer, writer/readers (WR), and chromatin remodeler/readers (CRR) in efforts to determine the effect of epigenetic function (chromatin modification) on severity of neurological dysfunction. Simon Searchlight data repository was accessed for this study. We included data from a total of 71 participants with a MDEM, 15 with a disorder involving chromatin writer, 22 of WR, and 34 of CRR. Caregivers provided genetic records to afford molecular confirmation of the MDEM, and completed a Vineland Adaptive Behavior Scale and a survey regarding diagnostic/seizure history. Results showed that participants with MDEMs of CRR yielded lower adaptive functioning scores across all skill areas relative to the Writer group, with the exception of receptive communication. Higher proportion of the CRR group are nonverbal, cannot ambulate independently, and require emergent seizure treatment (rescue drugs, emergency room admissions) as compared to the Writer group. Those with disorder involving WR did not significantly differ across measures from either groups. Findings highlight severity in neurological dysfunction, including seizure risk, can vary as a function of the disrupted epigenetic machinery. Results underscore the need for systematic research to identify epigenetic processes involved in the pathogenesis of neurodevelopmental disorders.