A novel de novo frameshift variant in the CHD2 gene related to intellectual and developmental disability, seizures and speech problems

Abstract

Background
The chromodomain helicase DNA‐binding protein 2 ( CHD2 ) is a member of the ATP‐dependent chromatin remodelling family of proteins, which are critical for the assembly and regulation of chromatin. De novo variants and deletions in the CHD2 gene have been associated with childhood‐onset developmental and epileptic encephalopathies type 94 (DEE 94). This study reports a novel deleterious de novo heterozygous frameshift insertion variant in the CHD2 gene.

Methods
The causative variant was diagnosed using whole‐exome sequencing. Sanger sequencing and cosegregation analysis were applied to confirm the candidate variant. Multiple in silico analysis tools were employed to interpret the variant using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines.

Results
A de novo deleterious variant, NM_001271.4:c.1570dup (NP_001262.3:p.Ser524PhefsTer30), in the CHD2 gene, was identified in a 16‐year‐old boy with an intellectual and developmental disability, seizures and speech problems. The de novo occurrence of the variant was confirmed by segregation analysis in the family.

Conclusion
The findings of this study expand the existing knowledge of variants of the CHD2 gene and provide a detailed phenotype associated with this gene. These data could have implications for genetic diagnosis and counselling in similar conditions. Moreover, this information could be useful for therapeutic purposes, including the proper administration of medication to control epilepsy.

Full text

Mol Genet Genomic Med. 2023;00:e2305.
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https://doi.org/10.1002/mgg3.2305
wileyonlinelibrary.com/journal/mgg3
Received: 21 February 2023
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Revised: 23 September 2023
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Accepted: 13 October 2023
DOI: 10.1002/mgg3.2305
ORIGINAL ARTICLE
A novel de novo frameshift variant in the CHD2 gene
related to intellectual and developmental disability,
seizures and speech problems
AtefehMir1
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YongjunSong2
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HaneLee2
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ZakiyeNadeali1
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Mohammad AminTabatabaiefar1,3,4
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
1Department of Genetics and Molecular
Biology, School of Medicine, Isfahan
University of Medical Sciences, Isfahan,
Iran
2Division of Medical Genetics, 3Billion
Inc, Seoul, South Korea
3Pediatric Inherited Diseases
Research Center, Research Institute
for Primordial Prevention of
Noncommunicable Disease, Isfahan
University of Medical Sciences, Isfahan,
Iran
4GenTArget Corp (GTAC), Deputy
of Research and Technology, Isfahan
University of Medical Sciences, Isfahan,
Iran
Correspondence
Mohammad Amin Tabatabaiefar,
Department of Genetics and
Molecular Biology, School of Medicine
and Pediatric Inherited Diseases,
Research Center, Research Institute
for Primordial, Prevention of Non-
Communicable Disease, University of
Medical Sciences, Isfahan 81746-73461,
Iran.
Email: tabatabaiefar@med.mui.ac.ir
Funding information
Isfahan University of Medical Sciences,
Grant/Award Number: 3991102
Abstract
Background: The chromodomain helicase DNA-binding protein 2 (CHD2) is a
member of the ATP-dependent chromatin remodelling family of proteins, which
are critical for the assembly and regulation of chromatin. De novo variants and
deletions in the CHD2 gene have been associated with childhood-onset devel-
opmental and epileptic encephalopathies type 94 (DEE 94). This study reports a
novel deleterious de novo heterozygous frameshift insertion variant in the CHD2
gene.
Methods: The causative variant was diagnosed using whole-exome sequencing.
Sanger sequencing and cosegregation analysis were applied to confirm the can-
didate variant. Multiple in silico analysis tools were employed to interpret the
variant using the American College of Medical Genetics and Genomics and the
Association for Molecular Pathology guidelines.
Results: A de novo deleterious variant, NM_001271.4:c.1570dup (NP_001262.3:p.
Ser524PhefsTer30), in the CHD2 gene, was identified in a 16-year-old boy with
an intellectual and developmental disability, seizures and speech problems. The
de novo occurrence of the variant was confirmed by segregation analysis in the
family.
Conclusion: The findings of this study expand the existing knowledge of vari-
ants of the CHD2 gene and provide a detailed phenotype associated with this
gene. These data could have implications for genetic diagnosis and counselling
in similar conditions. Moreover, this information could be useful for therapeutic
purposes, including the proper administration of medication to control epilepsy.
KEYWORDS
CHD2, DEE, developmental delay, duplication, epilepsy, intellectual disability, Iran

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1
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INTRODUCTION
Chromodomain helicase DNA-binding protein 2 (CHD2,
MIM: 602119) is a member of the CHD family, which
comprises an SNF2-related helicase/ATPase domain and a
chromatin-remodelling domain (chromodomain) (Lamar
& Carvill,2018). The CHD family of proteins affects the ex-
pression of genes by modification of chromatin structure,
leading to alterations of the accessibility of transcriptional
regulators to the DNA template (Liu etal., 2015; Wilson
etal.,2021). De novo variants and deletions in the CHD2
gene have been reported to be associated with a severe
form of neurodevelopmental disorders with a broad range
of phenotypic variabilities, such as intellectual disability
(ID), developmental delay (DD), autism spectrum disor-
der (ASD), microcephaly, behavioural abnormalities, fa-
cial dysmorphisms and several types of epilepsy known as
Developmental and Epileptic Encephalopathy-94 (DEE-94,
MIM No. 615369) (Chen etal.,2020; Thomas etal.,2015a;
Verhoeven etal., 2016). Developmental and epileptic en-
cephalopathies (DEEs) are therefore a heterogeneous
group of disorders, usually early-onset and present in the
first months of life. They are often characterized by severe
epileptic seizures and abnormalities in the electroenceph-
alogram (EEG) against a background of developmental
impairment that tends to worsen as a consequence of epi-
lepsy. The aetiologies of DEEs can be both nongenetic and
genetic. The genetics of DEEs have been linked to variants
in many genes involved in various functions including
cell migration, proliferation, organization, neuronal excit-
ability and synaptic transmission and plasticity (Guerrini
etal.,2023). DEE-94 is a severe form of epilepsy character-
ized by the onset of multiple seizure types in the first few
years of life with cognitive regression, impaired intellectual
development and a poor prognosis (Carvill etal.,2013).
In general, recognition of the genetic entity will allow
for earlier diagnosis and enable the development of tar-
geted therapies (Thomas et al., 2015b). An increasing
number of patients diagnosed with DEE using genetic test-
ing, such as whole-exome sequencing (WES), reflects the
importance of conducting these examinations in patients
with epilepsy (Heyne et al., 2018; Wright et al., 2018).
Importantly, patients with DEE could benefit from a pre-
cision medicine approach to reduce the overall burden of
epilepsy (Raga etal.,2021).
This study reports a novel de novo heterozygous single
base pair duplication causing a frameshift in the CHD2
gene in a 16-year-old boy diagnosed with an intellectual
and developmental disability, seizures and speech prob-
lems using whole-exome sequencing (WES) leading to the
confirmation of the diagnosis of Developmental Epileptic
Encephalopathy-96 (DEE-96) and expanding the muta-
tional and clinical knowledge on the CHD2 gene.
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SUBJECTS AND MATERIALS
2.1
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Subject and DNA extraction
A consanguineous Iranian family with a son with a severe
neurological disorder was recruited to this study. The sub-
ject's medical history was obtained, genetic counselling was
performed and the pedigree was drawn by the ‘Progeny’ soft-
ware (Progeny Software, LLC). Peripheral blood was taken
after getting informed written consent from the legal guard-
ian. DNA extraction was done using the DNSol Miniprep
Kit provided by ROJET ECH NOL OGIES company, Tehran,
Iran. This study has been approved by the Ethics Committee
of the Isfahan University of Medical Science, Isfahan, Iran
(Ethics code: IR.MUI.MED.REC.1400.042).
2.2
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Exome capture, WES and variant
prioritization
Exome capture, whole-exome sequencing and vari-
ant prioritization was performed by 3billion, inc, Seoul,
Korea. Exome capture was performed using xGen Exome
Research Panel v2 (Integrated DNA Technologies,
Coralville, Iowa, USA). Whole-exome sequencing was
performed using NovaSeq 6000 (Illumina, San Diego, CA,
USA), and sequence alignment was done to the Genome
Reference Consortium Human Build 37 (GRCh37) and
revised Cambridge Reference Sequence (rCRS) of the mi-
tochondrial genome. The variant interpretation was per-
formed using the EVIDENCE software (Seo etal.,2020) to
prioritize variants based on the guideline recommended by
the American College of Medical Genetics and Genomics
(ACMG) and the Association for Molecular Pathology
(AMP) (Richards et al., 2015) in relation to the patient
phenotypes. Only clinically significant variants associated
with the patient clinical manifestations were considered.
2.3
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Sanger sequencing and
Cosegregation and in silico analysis
The candidate variant was confirmed using Sanger se-
quencing, and cosegregation analysis was performed on
the family. Specific primers for the variant were designed
using the Primer3 online tool (Primer3web, version 4.1.0)
and validated by online tools such as Primer-BLAST
(Ye etal., 2012), MFEprimer3.1 (Wang et al.,2019) and
SNPCheck (gene tools, SNPCheck V3). The used primer
sequences are listed in Table1.
We used the Genome Aggregation Database (gnomAD
v2.1.1) and Iranome (http:// www. irano me. ir/ ) for popula-
tion allele frequency analysis. The potential pathogenicity of

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the variants was assessed using the NMDEscPredictor server
(https:// nmdpr edict ion. shiny apps. io/ nmdes cpred ictor/ ).
The NCBI Constraint-based Multiple Alignment Tool
(COBALT) server (version 1.22.0) was used for the anal-
ysis of domains conservation (https:// www. ncbi. nlm. nih.
gov/ tools/ cobalt/ cobalt. cgi? CMD= Web ). ACMG classifi-
cation was performed by using the Varsome online tool
(https:// varso me. com/ ). The schematic view of the CHD2
protein is from Human Protein Reference Database,n.d.
(http:// www. hprd. org/ ).
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RESULTS
3.1
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Subject
The proband (Figure1b) is a 16-year-old boy with a severe
intellectual disability (ID). He was born at term with nor-
mal vaginal delivery. He experienced benign neonatal sleep
myoclonus (BNSM) 6 days after birth that repeated until
8 months of age. He had seizures from 9 months of age,
which were recurrent, and controlled by Phenobarbital
(100 mg) and Sodium valproate (500 mg) at the time of
this study. By using Lamotrigine medication, he presented
Stevens–Johnson syndrome (SJS) symptoms. He also ex-
perienced recurrent vomiting during infancy and exces-
sive crying. In addition, he had a developmental delay. His
head circumference was 34 at birth, but it was normal in
the last assessment at the age of 12 months. He presents
speech problems and speaks limited words. He shows a
noncommunicative and silent personality. He has an ataxic
gait and upper limb muscular weakness. He sometimes pre-
sents behavioural problems, such as aggressive behaviour,
impatience and hallucinations. His facial features include
low-set ears, synophrys and a protruding chin. He was born
from consanguineous parents and has two sisters without
medical issues. There is a family history of ID, seizures, mi-
crocephaly, hearing loss, etc. in the pedigree (Figure1a).
Primer name 5′ → 3′ sequences Product size
Forward- CHD2 TTGTG AAG CAT TGG TGT CGTT 395 bp
Reverse- CHD2 ACTGA TGA TCT ACT GAA GGCTTTA
TABLE  Primer sequences for
Sanger sequencing and cosegregation
analysis.
FIGURE  (a) The pedigree of the studied family. (b) The photo of the proband. (c) Co-segregation data of the identified variant in the
family.

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3.2
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Sequencing and in silico findings
Exome sequencing revealed a deleterious heterozy-
gote variant (Table2), NM_001271.4:c.1570dup
(NP_001262.3:p.Ser524PhefsTer30), in the CHD2
gene related to Developmental and Epileptic
Encephalopathy-94 (DEE-94). Sanger sequencing and
cosegregation analysis revealed that none of the healthy
parents harboured the variant NM_001271.4:c.1570dup
(NP_001262.3:p.Ser524PhefsTer30), which confirmed
the variant occur in the patient in a de novo state
(Figure1c).
The variant was not found in the gnomAD and
Iranome database. Multiple in silico analysis tools
showed deleterious effects of the candidate variant on
the encoded protein. Table2 shows the sequence and in
silico findings of the candidate variant. It is predicted to
result in a loss or disruption of the normal protein func-
tion through nonsense-mediated decay (NMD) and pro-
tein truncation (Figure2). The COBALT server showed
the downstream domains are highly conserved in multi-
ple organisms. According to the ACMG guideline of vari-
ant classification (Richards etal., 2015), the identified
variant was classified as ‘pathogenic’ because of having
these criteria for the pathogenicity: PVS1(null variant),
PP5 (ClinVar classifies this variant as Pathogenic), PM2
(variant not found in gnomAD), PS2 (de novo in a pa-
tient with no family history), and PM1 (located in a crit-
ical domain).
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DISCUSSION & CONCLUSION
Chromodomain helicase DNA-binding protein 2 (CHD2)
mutation-related epilepsy was first described in 2009 by
Capelli et al (Capelli et al., 2012). By the clinical appli-
cation of next-generation sequencing technologies, the
number of patients diagnosed with epilepsy related to the
CHD2 gene variants has increased (Chénier etal., 2014;
Galizia etal.,2015; Suls etal.,2013; Thomas etal.,2015a).
The CHD2 gene seems to play an important role in the
brain by altering gene expression as a consequence of the
chromatin remodelling process. The CHD2 gene contains
39 exons that encode as large as 1828 amino acid tran-
scripts (Liu etal.,2015).
The present study identified a de novo vari-
ant NM_001271.4:c.1570dup (NP_001262.3:p.
Ser524PhefsTer30) in the CHD2 gene in a 16-year-old
boy with an intellectual and developmental disability,
seizures and speech problems. The identified variant is
located within exon 14 of 39 in the encoded region of
serine 524 and has a nonsense consequence as a result
of an insertion frameshift variant, leading to premature
TABLE  Genomic and in silico information on identified variant.
Genomic position Cytoband
Variant
type HGVS*Protein change Zygosity
gnomAD
frequency
Iranome
frequency
Predicted
consequence
Variant
classification
15-93,496,653-C-CT
(GRCh37)
15q26.1-15q26.1 Nonsense CHD2(NM_001271.4):c.1570dup p.Ser524PhefsTer30 Heterozygous Not Found Not Found Frameshift
insertion
Pathogenic
*HGVS nomenclature; the recommendations for describing sequence variants in DNA, RNA, and protein sequences.

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MIR etal.
stop codon 30 residue after the variant position. The
premature stop codon results in the loss of a large part
of the gene product consisting of the last 25 exons en-
coding for the critical domains including the DEXDc
domain (which contains the ATP-binding region) and
its downstream domains such as HELICc (helicase su-
perfamily c-terminal domain). It is expected to result
in a truncated protein product that can be undergoing
nonsense-mediated decay (NMD) mechanism (Brogna &
Wen,2009). Notably, conservation studies showed down-
stream domains to be highly conserved (Human Protein
Reference Database,n.d.). As previously described, hap-
loinsufficiency of the CHD2 protein leads to neurologi-
cal conditions such as epilepsy. Therefore, the findings of
the present study confirmed the pathogenic state of this
loss-of-function variant in the CHD2 gene. In 2020, Chen
et al. presented the largest case series of patients with
CHD2-related epilepsy (Chen etal.,2020), and also De
Maria etal. in 2021, reported 18 new patients and got the
results that the median age of seizure onset in 92% of pa-
tients was 2.5 years, and there was no clear association be-
tween genotypes and phenotypes (De Maria etal.,2022).
As ClinVar and HGMD databases showed, all the re-
ported variants downstream of the identified variant in
the present study, are related to Developmental Epileptic
Encephalopathy-96 (DEE-96). The patient of the present
study also suffers from an intellectual and developmental
disability, seizures and speech problems that are known
as DEE-96 disorder. The identified patient has some sub-
tle facial features such as; low-set ears, synophrys and
protruding chin that could be considered in precise di-
agnosis applications. In addition, currently, no specific
guidelines regarding the choice of specific antiseizure
medications exist. Most individuals remain refractory to
treatment and require multiple antiseizure medications.
Epilepsy manifestations in the identified patient of the
current study were controlled by Phenobarbital (100 mg)
and Sodium valproate (500 mg), suggesting an appropri-
ate treatment approach in such patients to reduce the
overall burden of epilepsy.
In conclusion, the present study revealed a de
novo deleterious variant, NM_001271.4:c.1570dup
(NP_001262.3:p.Ser524PhefsTer30), in the CHD2 gene,
in a 16-year-old boy with an intellectual and develop-
mental disability, seizures and speech problems. The
findings expand the existing knowledge of variants of
the CHD2 gene and provide a detailed phenotype asso-
ciated with this gene. The findings of this study could
have implications for genetic diagnosis, therapeu-
tic aims and genetic counselling in epileptic patients.
Moreover, these data can be useful for therapeutic pur-
poses, including the proper administration of medica-
tion to control epilepsy.
AUTHOR CONTRIBUTIONS
Atefeh Mir was involved in the recruitment of patient
and family members, mutation screening and segregation
analysis in families by Sanger sequencing, and writing the
first draft of the manuscript; Yongjun Song and Hane Lee
were involved in performing whole-exome sequencing
and data analysis; Zakiye Nadeali was involved in par-
ticipating in blood sampling of the patient and his family,
and writing the first draft of the manuscript; Mohammad
Amin Tabatabaiefar was involved in the design and super-
vision of the research, review and editing the first draft of
the manuscript.
ACKNO WLE DGE MENTS
We sincerely thank the family who participates in this
study. We are sincerely grateful to 3Billion Inc., Seoul,
South Korea, for performing the whole exome sequenc-
ing. The Isfahan University of Medical Sciences also sup-
ported the study, Isfahan, Iran (Grant No. 3991102). This
is a part of A. M.'s Ph.D. thesis.
FUNDING INFORMATION
This study was funded by the Isfahan University of
Medical Sciences, Isfahan, Iran (Grant No. 3991102) and
research collaboration with 3Billion Inc., Seoul, South
Korea.
FIGURE  NMD prediction of the
c.1570dup variant in the CHD2 gene. Red-
colored regions are critical for NMD.

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CONFLICT OF INTEREST STATEMENT
The authors declare that they have no conflict of interest.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are in-
cluded in this published article, and the raw data that
support the findings of this study are available from the
corresponding author upon reasonable request. The vari-
ant submitted in ClinVar database.
ETHICS STATEMENT
The research was performed in accordance with the
Declaration of Helsinki and with the approval of the eth-
ics board of the Isfahan University of Medical Sciences
(Ethics code: IR.MUI.MED.REC.1400.042).
CONSENT TO PARTICIPATE
All participant's legal guardians consented to participate
after being informed of the nature of the research.
ORCID
Mohammad Amin Tabatabaiefar https://orcid.
org/0000-0003-0730-750X
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How to cite this article: Mir, A., Song, Y., Lee, H.,
Nadeali, Z., & Tabatabaiefar, M. A. (2023). A novel
de novo frameshift variant in the CHD2 gene
related to intellectual and developmental disability,
seizures and speech problems. Molecular Genetics
& Genomic Medicine, 00, e2305. https://doi.
org/10.1002/mgg3.2305