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studied are ID and ASD, which when taken together, are among the most common disorders worldwide,
affecting 1%-3% of the global population [32,33] .

Genetic sequence-based epigenetic causation in NDDs
The involvement of epigenetic processes in NDDs was first ascertained by the observation that several
causative genes for monogenic NDD syndromes encode factors involved in epigenomic regulation, thereby
directly implicating epigenomic deregulation as an etiology. We previously conducted a substantial review of
[30]
NDDs caused by defects in genes that encode epigenetic factors , showing how such genetic defect-caused
epigenomic deregulation leads to varied NDDs. Following the recognition that genetic mutations resulting
in haploinsufficiency for proteins that are key epigenetic regulatory factors, or dominant negative forms
thereof, can cause NDDs, focused studies probing the extent of causation found that epigenetic deregulation
[34]
is indeed a significant etiology for NDDs , not limited to syndromic NDDs [35-37] .

Environment-based epigenetic causes of NDDs
On a different track, twin studies showed that environmental exposures play a key role in NDD causation.
Studying monozygotic twins displayed variation in behavior for psychiatric disorders, which was more
[38]
prominent with age . Currently, it is increasingly well recognized that adverse prenatal environments, such
as exposure to maternal stress, viral infections, drugs, and toxins, can disrupt normal brain development and
have lasting consequences on the structure and function of the brain [39,40] . Moreover, prenatal adversity can
significantly increase the risk of developing mental disease in later life, including SCZ, depression, anxiety,
and autism, among others [16,41,42] . Interestingly, maternal stress during pregnancy has also been associated
with the increased risk of the development of many neuropsychiatric disorders in the offspring besides SCZ,
[43]
including depression, autism, and anxiety .
The epigenome is highly susceptible to environmental exposures (e.g., maternal stress, toxins, drugs,
pollutants) during early prenatal development, when extensive epigenetic reprogramming (resetting the
human epigenome for naive pluripotency) and epigenetic programming (epigenetic alterations driving
[44]
cellular differentiation) take place, to establish cell- and tissue-specific gene expression . It is therefore
hypothesized that interference with these processes during early embryogenesis can significantly impact early
gene programming in the developing embryo [44,45] . In fact, there is a growing body of evidence suggesting
that maternal exposures to epigenome regulation influencers such as “epi-diet” and “epi-drugs” - food
substances and pharmacological compounds that influence the epigenome, respectively - are able to impact
[39]
fetal outcome with respect to NDD .

Chromatin remodeling as important for plasticity during brain development and function
The ability of intrinsic and extrinsic factors that act via epigenetic mechanisms to effect NDD causation
is explained by the fact that the brain is the most plastic of all organs. The developing and functioning
brain must continuously adapt to external stimuli and respond to it. The response process, though not yet
fully understood, almost certainly involves large-scale and fine-tuned chromatin changes that cause both
structural and functional change at the molecular and cellular level during regulation of gene expression.
Epigenetic regulatory processes are mechanistically capable of a range of fine-tuning of gene expression [46,47] .
This in turn makes any change in the enzymes that lay out these processes a key susceptibility factor for
NDD.

Epigenetic modifications of chromatin delivers dynamic regulation of gene expression via acetylation,
[48]
phosphorylation, methylation, ubiquitination and sumoylation . Thus, disturbance of this equilibrium in
the brain or central nervous system leads to NDDs with complicated phenotypes [16,29] . While roles in NDD
[49]
are found for all chromatin remodelers , we will focus here on that of the CHD family of SF-2 ATP-ase
dependent remodelers.