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Page 316 Yasin et al. J Transl Genet Genom 2020;4:307-19 I https://doi.org/10.20517/jtgg.2020.30

As we noted for the human cellular model studies, there is a discrepancy in results for the mouse models.
The molecular, physiological and behavioral characterizations conducted by each group were not the same,
and hence, we cannot make definitive conclusions about the lack of sameness. However, it is remarkable that
macrocephaly was commonly observed. Behavioral phenotypes were also reported by the majority of the
groups.

We caution that the findings reported from these studies are a consequence of their setting out to study one
condition only, viz, ASD, and therefore they do not rule out a wider role for Chd8 deficiency. Finally, we
note that as is presumed for humans, the mouse homozygous deletion is embryonic lethal, which serves to
underscore the importance of Chd8 in development.

CONCLUSION
The importance of correct epigenetic regulation and normal epigenomic state as integral to normal nervous
development and function is now recognized [30,39,53] . Among the best known epigenomic regulatory
processes, chromatin remodeling or modification is gaining significance as a key transcriptional regulatory
process with widespread activity. The CHDs are a group of nine proteins encoded by the corresponding
genes CHD1-9, which comprise one of the four main chromatin remodeling protein families, viz., the
chromodomain helicase DNA-binding protein family. Of the nine CHDs, five are currently known to cause
autosomal dominant syndromic NDDs with a diverse range of phenotypes including ID, ASD, neurological
defects, skeletal defects, macrocephaly, and other major congenital anomalies. The fact that all five known
CHD syndromes are autosomal dominant underscores the importance of these proteins in development.

The remarkable range of phenotypes presented, however, also indicates that the CHDs have widespread
developmental roles. Though a number of cellular and model organism studies have attempted to map the
molecular role of CHDs, their results also indicate a broad role for CHDs as epigenomic programmers. As we
have laid out at the beginning of this review, epigenetic regulation is a complex process involving several key
mechanisms that do not act alone, but rather as a concert of processes able to provide fine-tuned response
to environmental states and developmental goals. It is important to keep this in mind when discussing the
role of any one or a class of epigenetic regulatory proteins. Thus, given these contexts, extracting the precise
pathophysiological roles of any one of the CHDs will be challenging.

In this paper, we overviewed the ability of the environment to influence the epigenome, highlighting
the notion that therefore, externally induced environmental changes may hold promise to correct
constitutional genetic insults that perturb the normal epigenome. However, we are as yet unaware of any
results demonstrating that such a curative strategy may have an impact on NDDs caused by CHD defects.
Rather, the widespread and fundamental nature of CHD control on development argues against easily being
able to environmentally correct CHD genetic defects. Nevertheless, we end this review by calling for such
exploratory studies in model systems. A large number of reports in the past two decades have proven that
CHDs have a key regulatory function in development and control, which therefore prompts the call for
creative and wide-ranging research into possible therapeutic methods.

DECLARATIONS
Authors’ contributions
Provided figure and assisted with literature review: Yasin H
Conceived and wrote the manuscript: Zahir FR

Availability of data and materials
Not applicable.