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Page 312 Yasin et al. J Transl Genet Genom 2020;4:307-19 I https://doi.org/10.20517/jtgg.2020.30

Table 1. NDDs identified that are caused by CHD gene defects
CHD Distinguishing features/comment NDD that it is causative for
Subfamily 1
CHD1 Prototype - Two chromodomains and a SNF-2 ATPase Pilarowski-Bjornsson syndrome
domain Developmental Delay,
And DNA binding domain Autism Spectrum Disorder,
Seizures
CHD2 Intellectual Disability, Epilepsy, Developmental Delay, Autism Spectrum
Disorder
Subfamily 2
CHD3 No DNA binding domain Snijders Blok-Campeau syndrome.
Two PHDs motifs. Developmental Delay, Intellectual Disability,
CHD3, CHD4 and CHD5 form the core ATPase unit of Seizures
CHD4 the NuRD chromatin remodeling complex Sifrim-Hitz-Weiss syndrome.
Intellectual Disability
CHD5 Yet unknown
Subfamily 3
CHD6 Contain a variety of additional domains to the Yet unknown
CHD7 prototype CHARGE syndrome, Autism Spectrum Disorder
CHD8 SANT domains, BRK domains, Conserved region Zahir Friedman syndrome, Autism Spectrum Disorder, Schizophrenia,
domains
Intellectual Disability
Developmental Delay
Seizures
CHD9 Yet unknown
NDD: neurodevelopmental disorder

CHDS AND NEURODEVELOPMENTAL DISEASE
CHDs known to cause NDDs
CHDs were first implicated in NDDs in the same way that epigenetics in general was recognized to be
a significant etiological factor, by identifying causative genes for NDDs that happened to encode CHD
proteins. The first to be so identified was CHD7, as the causative gene for CHARGE syndrome (CHARGE, an
acronym for the common constellation of phenotypes presented - coloboma, heart defects, atresia choanae,
[50]
retardation of growth, genital abnormalities, and ear abnormalities) . After finding deletions in the gene
in a small cohort of CHARGE patients by using a genome screen, a subsequent targeted sequencing of
the CHD7 gene confirmed it to be the causative gene for CHARGE syndrome. However, while CHARGE
syndrome is a developmental disorder, it is not considered primarily an NDD, since neurological phenotypes
are not distinguishing. The next CHD gene identified to be disease-causing, and the first causative gene for an
NDD, was CHD8, which was identified as one of two critical genes for a novel NDD syndrome first reported
[51]
in 2007 . This finding was also the result of a genome screen in patients with ID. Subsequent work showed
the gene to be the major causative factor for this syndrome, which we suggest be called Zahir Friedman
[52]
syndrome (ZFS) .
Recently, with the widespread use of next-generation sequencing technologies, several more CHDs were
identified as causative for NDD [23,53] [Table 1]. Particularly, we note that syndromic NDDs caused by CHD1
[54]
[55]
(Pilarowski-Bjornsson syndrome- PILBOS) , CHD3 (Snijders Blok-Campeau syndrome -SNIBCPS)
[56]
and CHD4 (Sifrim-Hitz-Weiss syndrome - SIHIWES) , were identified in the past few years as a result
of efforts to match genotype to phenotype using global repositories such as GeneMatcher. We anticipate
that syndromic NDDs may be soon identified for CHD5, CHD6 and CHD9 as well, as genotype-phenotype
correlations and genome screening for idiopathic patients with NDDs become ever more accessible globally.

In the past decade, there were also separate large-scale sequencing efforts to identify causative genes for ASD,
which identified sequence mutations in CHD8 that can contribute to as much as 0.5% of ASD. While we
[52]
posit that patients with sequence mutations in CHD8 also display ZFS , we do not rule out the possibility of
a nuanced disease expression profile depending on whether the gene has undergone a deletion or sequence