Epigenetics of cognition and behavior: insights from Mendelian disorders of epigenetic machinery

Abstract

Epigenetics, one mechanism by which gene expression can change without any changes to the DNA sequence, was described nearly a century ago. However, the importance of epigenetic processes to neurodevelopment and higher order neurological functions like cognition and behavior is only now being realized. A group of disorders known as the Mendelian disorders of the epigenetic machinery are caused by the altered function of epigenetic machinery proteins, which consequently affects downstream expression of many genes. These disorders almost universally have cognitive dysfunction and behavioral issues as core features. Here, we review what is known about the neurodevelopmental phenotypes of some key examples of these disorders divided into categories based on the underlying function of the affected protein. Understanding these Mendelian disorders of the epigenetic machinery can illuminate the role of epigenetic regulation in typical brain function and can lead to future therapies and better management for a host of neurodevelopmental and neuropsychological disorders.

Attention challenges in Kabuki syndrome

“…With further research looking into specific behavioural profiles for each MDEM, more similarities are being brought to light (Ng et al . 2023a). Notably, attention deficits are emerging as a common feature.…”

Etiologic heterogeneity, pleiotropy, and polygenicity in behaviorally defined intellectual and developmental disabilities

“…Beyond the mGluR network, epigenetic factors are also considered key mediators in many neurodevelopmental disorders. Ng and colleagues provide a systematic review of the evidence for alterations in epigenetic machinery that contribute to risk for Mendelian disorders characterized by cognitive dysfunction and behavioral issues [ 13 ]. They propose that by comprehensively characterizing similarities and differences in symptomatology across numerous Mendelian Disorders of the epigenetic machinery, as well as focusing on common epigenetic functions of proteins like histone methyltransferases and chromatin remodelers, we can begin to understand the complicated genomic and epigenetic landscape underlying cognitive and behavioral traits associated with IDDs.…”

Editorial: Characterizing the neurobehavioral phenotype of mendelian disorders of epigenetic machinery

“…Accordingly, there has been a growing recognition that collectively MDEMs may represent a sizeable proportion of individuals with neurodevelopmental disability. Towards this end, research in MDEMs and the associated epigenetic modification–heritable alterations in gene expression without modifications to the DNA sequence–can shed light on the role of epigenetic regulation in the pathogenesis of developmental disorders in addition to typical brain development and growth ( Ng et al, 2023 ).…”