# CHD2 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The *CHD2* gene, located at 15q26.1, encodes an ATP-dependent chromatin remodeler crucial for transcriptional regulation and histone variant deposition (H3.3). Pathogenic variants, primarily loss-of-function, lead to haploinsufficiency and are a significant cause of neurodevelopmental disorders, most notably developmental and epileptic encephalopathies (DEE), intellectual disability (ID), and autism spectrum disorder (ASD).
- *CHD2* mutations are strongly associated with specific epilepsy syndromes, including myoclonic-atonic epilepsy (MAE) and Lennox-Gastaut syndrome (LGS), often characterized by photosensitivity. These mutations disrupt neuronal development and synaptic plasticity, contributing to network hyperexcitability.
- The *CHD2* gene locus features a unique bidirectional promoter architecture with the *CHASERR* long non-coding RNA, which acts as a negative regulator of *CHD2* expression. Dysregulation of this feedback loop, such as through *CHASERR* deletion, can lead to pathogenic increases in CHD2 protein levels.
- Beyond neurological conditions, *CHD2* alterations are implicated in hematological malignancies like Chronic Lymphocytic Leukemia (CLL) and pediatric high-grade glioma, where CHD2 functions as a tumor suppressor by maintaining chromatin accessibility and genome stability.
- Emerging diagnostic tools include identifying a specific DNA methylation "episignature" associated with *CHD2* variants, aiding in the classification of variants of uncertain significance. Therapeutic strategies are largely symptomatic, but investigational approaches include gene therapy and antisense oligonucleotides targeting *CHD2* expression.

---

## Executive Summary & Key Metadata

The chromodomain helicase DNA-binding protein 2 (CHD2) is an ATP-dependent chromatin remodeling enzyme encoded by the *CHD2* gene. As a member of the CHD family (subfamily II), CHD2 is essential for the regulation of chromatin architecture, nucleosome assembly, and transcription. Pathogenic variants in *CHD2* are a well-established cause of a broad spectrum of neurodevelopmental phenotypes, most notably developmental and epileptic encephalopathies (DEE), intellectual disability (ID), and autism spectrum disorder (ASD). Beyond neurology, *CHD2* alterations are implicated in hematological malignancies, pediatric glioma, and other cancers. This reference manual provides a comprehensive, biophysically detailed analysis of the *CHD2* gene, from its genomic organization and protein domain architecture to its molecular functions, clinical mutational spectrum, and therapeutic implications.

| **Attribute** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | CHD2 |
| **UniProt Accession** | O14647 |
| **Representative PDB ID** | true (Structural models available via homology; full-length structure not yet experimentally resolved) |
| **Chromosomal Locus** | 15q26.1 |
| **Primary Molecular Function** | ATP-dependent chromatin remodeling; nucleosome sliding; histone H3.3 deposition; transcriptional regulation |
| **Disease & Pathology Associations** | Developmental and epileptic encephalopathy (DEE), Intellectual disability (ID), Autism spectrum disorder (ASD), Myoclonic epilepsy, Lennox-Gastaut syndrome, Chronic lymphocytic leukemia (CLL), Pediatric high-grade glioma, Breast implant-associated ALCL |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Location and Gene Structure

The *CHD2* gene is located on the long (q) arm of chromosome 15 at cytogenetic band 15q26.1. The genomic coordinates (GRCh38/hg38) span approximately 15q26.1, from base pair 92,900,000 to 93,030,000 (minus strand). The gene is large, encompassing roughly 130 kilobases (kb) of genomic DNA, and contains 40 exons that encode a mature messenger RNA (mRNA) of approximately 8.5 kb. The coding sequence (CDS) is approximately 5,628 base pairs, translating into a large protein of 1,828 amino acids with a predicted molecular weight of ~210 kDa [1, 2].

The *CHD2* locus is situated in a gene-dense region of chromosome 15. Its genomic neighborhood includes the *CHASERR* (CHD2 adjacent, suppressor of enhancer RNAs) long non-coding RNA (lncRNA) gene, which is transcribed from the opposite strand and overlaps the *CHD2* promoter region. This arrangement is critical for the cis-regulation of *CHD2* expression. The *CHASERR* lncRNA acts as a negative regulator of *CHD2*, and its deletion leads to increased *CHD2* expression, which is itself pathogenic [3, 4].

### 1.2 Promoter Architecture and Regulatory Elements

The promoter region of *CHD2* is characterized by a CpG island, a hallmark of constitutively expressed or developmentally regulated genes. The core promoter contains canonical TATA and initiator (Inr) elements, as well as binding sites for ubiquitous transcription factors such as Sp1. However, the most distinctive regulatory feature is the presence of the *CHASERR* lncRNA transcription start site (TSS) within the *CHD2* promoter region. Transcription of *CHASERR* from the opposite strand interferes with *CHD2* promoter activity, establishing a negative feedback loop. This bidirectional promoter architecture is a key mechanism for fine-tuning CHD2 protein levels, as even a 50% reduction (haploinsufficiency) is pathogenic [3, 4, 5].

Enhancer elements for *CHD2* are distributed both upstream and within intronic regions. Chromatin state annotations (e.g., H3K27ac, H3K4me1) from ENCODE and Roadmap Epigenomics projects indicate active enhancer signatures in neural progenitor cells and the adult brain, aligning with the critical role of CHD2 in neurodevelopment. The 3' untranslated region (UTR) contains multiple microRNA (miRNA) binding sites and AU-rich elements (AREs) that regulate mRNA stability and translation.

### 1.3 Alternative Splicing and Isoforms

Alternative splicing of *CHD2* generates multiple transcript variants. The predominant transcript (ENST00000324856.9) encodes the full-length, canonical 1,828-amino acid protein. Several minor isoforms have been reported, primarily involving alternative splicing in the N-terminal region and the C-terminal domain. For instance, a splice variant lacking exon 5 results in a truncated chromodomain, potentially altering chromatin binding specificity. Another variant, which retains intron 38, introduces a premature stop codon, leading to a C-terminally truncated protein that may act in a dominant-negative manner. The functional significance of these minor isoforms remains under investigation, but their existence contributes to the complexity of CHD2-related phenotypes [<a href="#ref-6">6</a>].

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Primary Structure and Domain Organization

The CHD2 protein is a large, multi-domain chromatin remodeler. Its domain architecture, from the N-terminus to the C-terminus, is as follows:

1.  **N-terminal Region (aa 1-200):** Contains a poorly structured region with nuclear localization signals (NLS). Two NLSs have been identified, one bipartite (aa 120-137) and one monopartite (aa 190-196), which are essential for nuclear import [<a href="#ref-7">7</a>].
2.  **Tandem Chromodomains (aa 200-400):** Two chromodomains in tandem. These domains are responsible for binding to methylated histone tails, particularly H3K4me3, a mark of active promoters. This interaction anchors CHD2 to active chromatin regions.
3.  **SNF2-like ATPase Domain (aa 400-1100):** The catalytic core of the protein, belonging to the SNF2 family of ATPases. It is composed of two RecA-like lobes (DEXDc and HELICc). This domain couples ATP hydrolysis to the mechanical work of nucleosome sliding and remodeling.
4.  **Hinge Region (aa 1100-1300):** A less conserved region that connects the ATPase domain to the C-terminal domains. It may serve as a flexible linker.
5.  **C-terminal Chromo-like Domain (aa 1300-1400):** A single chromo-like domain that also contributes to histone binding.
6.  **DNA-binding Domain (DBD) (aa 1400-1600):** A region rich in basic residues that binds non-specifically to DNA, stabilizing the remodeler-nucleosome complex.
7.  **C-terminal BRK Domain (aa 1600-1828):** The BRK (Brahma and Kismet) domain is a signature motif of CHD proteins. Its function is not fully defined, but it is thought to mediate protein-protein interactions and is required for the recruitment of CHD2 to specific genomic loci.

### 2.2 Structural Biology and 3D Conformation

The full-length three-dimensional structure of human CHD2 has not been solved by X-ray crystallography or cryo-EM due to its size and intrinsic flexibility. However, high-resolution structures of individual domains, particularly the ATPase domain and chromodomains, have been obtained through homology modeling based on related CHD family members (e.g., CHD1). These models reveal a highly dynamic structure.

In its autoinhibited state, the ATPase domain is held in an open conformation by intramolecular interactions with the chromodomains and the C-terminal region. Upon binding to a nucleosome and histone H3, the protein undergoes a large conformational change, closing the ATPase domain around the DNA. This closure activates ATP hydrolysis, which generates the force to shift the DNA duplex relative to the histone octamer, thereby sliding the nucleosome along the DNA.

The tandem chromodomains form a globular structure with a hydrophobic cage that accommodates the tri-methylated lysine 4 of histone H3 (H3K4me3). This interaction is critical for targeting CHD2 to active gene promoters and enhancers [8, 9].

> **Interactive 3D Visualizer Callout Box**
>
> Explore the predicted 3D architecture of the CHD2 protein, including its chromodomains, ATPase motor, and C-terminal domains, using the interactive visualizer below. This tool allows for structural analysis of domain organization and mutation mapping.
>
> `[Interactive 3D Protein Visualizer: Load CHD2 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O14647)`

### 2.3 Catalytic Mechanism and Post-Translational Modifications

The ATPase activity of CHD2 is stimulated by the presence of nucleosomes and DNA. The hydrolysis of ATP is coupled to the directional movement of the remodeler along the nucleosome, leading to the sliding of the histone octamer. This process is essential for the establishment of proper nucleosome positioning and the maintenance of chromatin accessibility.

CHD2 is subject to various post-translational modifications (PTMs) that regulate its activity and stability. Phosphorylation by cyclin-dependent kinases (CDKs) has been shown to modulate its ATPase activity during the cell cycle. Ubiquitination and sumoylation are also predicted to occur, potentially targeting CHD2 for proteasomal degradation or altering its subcellular localization. Acetylation of lysine residues in the N-terminal region may influence its interaction with other chromatin factors.

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Chromatin Remodeling and Transcriptional Regulation

CHD2 is a core component of the transcriptional machinery. It is recruited to active promoters and enhancers, where it performs several functions:

- **Nucleosome Sliding:** CHD2 uses the energy from ATP hydrolysis to slide nucleosomes along DNA, thereby exposing or occluding transcription factor binding sites. This activity is crucial for the fine-tuning of gene expression.
- **Histone Variant Deposition:** CHD2 is a major chaperone for the histone variant H3.3. It facilitates the incorporation of H3.3 into chromatin at active gene bodies and regulatory elements. This deposition is essential for maintaining the epigenetic memory of active transcription [10, 11].
- **Chromatin Accessibility:** By remodeling nucleosomes, CHD2 increases the accessibility of chromatin to RNA Polymerase II and other transcription factors. This is particularly important for the rapid induction of immediate-early genes in response to neuronal activity [<a href="#ref-12">12</a>].

### 3.2 Role in Neurodevelopment and Neuronal Function

In the developing brain, CHD2 is essential for the proliferation and differentiation of neural progenitor cells (NPCs). It regulates the expression of genes involved in cell cycle exit, neuronal migration, and synaptogenesis. Studies using human embryonic stem cell (hESC) models have shown that CHD2 is required for the proper specification of cortical interneurons, a cell type that is dysfunctional in epilepsy and ASD [13, 14].

CHD2 haploinsufficiency in mouse models leads to a reduction in the number of parvalbumin-positive interneurons and impaired synaptic plasticity. At the synaptic level, CHD2 regulates the expression of genes encoding postsynaptic density proteins and neurotransmitter receptors. It is also involved in the homeostatic plasticity of synapses, a process that stabilizes neuronal activity. Disruption of this process, as seen in *CHD2* mutations, can lead to network hyperexcitability and seizures [15, 16].

### 3.3 Interaction Networks and Protein-Protein Interactions

CHD2 does not act in isolation. It is part of a large interactome that includes other chromatin remodelers, transcription factors, and histone modifiers. Key interacting partners identified through affinity purification and mass spectrometry include:

- **TET2:** CHD2 interacts with the DNA demethylase TET2 in hematopoietic stem and progenitor cells (HSPCs). This interaction is critical for the regulation of lineage-defining transcription factors. Loss of CHD2 or TET2 leads to aberrant DNA methylation and impaired hematopoiesis [<a href="#ref-17">17</a>].
- **RNA Polymerase II (Pol II):** CHD2 associates with the elongating form of Pol II, facilitating transcription elongation and co-transcriptional histone modification [<a href="#ref-18">18</a>].
- **Histone Chaperones:** CHD2 interacts with HIRA and other H3.3-specific chaperones to coordinate the deposition of H3.3.
- **Transcriptional Co-factors:** CHD2 interacts with various transcription factors, including those involved in neuronal development (e.g., LHX6, DLX2) and hematopoiesis (e.g., GATA1, RUNX1) [13, 17].

```mermaid
sequenceDiagram
    participant N as "Nucleosome (H3K4me3)"
    participant C as "CHD2 (Inactive)"
    participant C* as CHD2 (Active)
    participant P as "RNA Pol II"
    participant T as "TET2"
    N->>C: Binds via Chromodomains
    C->>C*: ATP Hydrolysis & Conformational Change
    C*->>N: Nucleosome Sliding & H3.3 Deposition
    C*->>P: Recruits & Stabilizes Pol II
    C*->>T: Interacts with TET2
    T->>N: DNA Demethylation (Active Enhancers)
    N-->>C: Remodeled Chromatin (Accessible)
```

### 3.4 Role in DNA Damage Response

CHD2 is recruited to sites of DNA double-strand breaks (DSBs). It facilitates the relaxation of chromatin at the break site, which is necessary for the recruitment of DNA repair factors such as 53BP1 and BRCA1. Cells deficient in CHD2 show increased sensitivity to ionizing radiation and defects in homologous recombination repair. This function links CHD2 to genome stability and tumor suppression [<a href="#ref-19">19</a>].

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Mutational Spectrum and Mechanisms

Pathogenic variants in *CHD2* are predominantly *de novo* loss-of-function (LoF) mutations, including nonsense, frameshift, and splice-site variants. These mutations lead to haploinsufficiency, where the single functional copy of the gene is insufficient to maintain normal cellular function. Missense mutations are also observed, often clustering in the ATPase domain and the chromodomains, where they disrupt catalytic activity or histone binding [20, 21].

The mutational landscape is broad, with no single dominant hotspot. However, recurrent mutations have been identified in the ATPase domain, particularly in the Walker A and Walker B motifs, which are essential for ATP binding and hydrolysis. Missense variants in these motifs often result in a dominant-negative effect, where the mutant protein can bind to nucleosomes but cannot remodel them, thereby blocking access for other remodelers [<a href="#ref-22">22</a>].

### 4.2 Clinical Phenotypes

The clinical spectrum of *CHD2*-related disorders is wide, ranging from mild ID to severe DEE. The core phenotype includes:

- **Epilepsy:** The most common presentation. Seizure types are variable and include myoclonic, atonic, tonic-clonic, and absence seizures. Photosensitivity is a distinctive feature, with seizures triggered by intermittent photic stimulation. *CHD2* mutations are a significant cause of myoclonic-atonic epilepsy (MAE) and Lennox-Gastaut syndrome (LGS) [23, 24].
- **Developmental and Epileptic Encephalopathy (DEE):** Characterized by early-onset seizures, developmental delay or regression, and cognitive impairment. The severity is often correlated with the type of mutation, with truncating mutations generally leading to more severe phenotypes [<a href="#ref-25">25</a>].
- **Intellectual Disability (ID):** Ranging from mild to profound. Speech and language development are particularly affected.
- **Autism Spectrum Disorder (ASD):** A significant proportion of individuals with *CHD2* mutations meet the diagnostic criteria for ASD.
- **Behavioral Problems:** Including hyperactivity, aggression, and anxiety.
- **Other Features:** Scoliosis, gastrointestinal dysmotility, and subtle facial dysmorphisms have been reported [26, 27].

### 4.3 Genotype-Phenotype Correlations

Establishing clear genotype-phenotype correlations has been challenging. However, some general trends are emerging:

- **Truncating Mutations (Nonsense, Frameshift):** Generally associated with more severe DEE and profound ID. These mutations almost always result in haploinsufficiency.
- **Missense Mutations in ATPase Domain:** Often associated with a similar, albeit sometimes milder, phenotype. The functional impact depends on the specific amino acid substitution and its location within the catalytic core.
- **Missense Mutations in Chromodomains:** May have a more specific effect on histone binding, potentially leading to a distinct clinical presentation with a higher prevalence of ASD.
- **Copy Number Variants (CNVs):** Whole-gene deletions or duplications of 15q26.1 encompassing *CHD2* result in haploinsufficiency and a phenotype similar to intragenic LoF mutations. The size of the deletion can influence the phenotype if additional genes are involved [<a href="#ref-1">1</a>].

### 4.4 Episignature and Diagnostic Utility

Recent advances in DNA methylation analysis have identified a specific "episignature" for *CHD2*-related disorders. This is a unique pattern of genome-wide DNA methylation that is characteristic of pathogenic *CHD2* variants. This episignature can be used as a diagnostic biomarker to classify variants of uncertain significance (VUS) and to identify patients with *CHD2* dysfunction who may have negative results on standard sequencing panels [2, 3].

## 5. Host-Pathogen & Viral Interactions

### 5.1 HIV-1 Replication

CHD2 has been identified as a positive regulator of HIV-1 gene expression. An insertional mutagenesis screen for host factors required for retroviral replication identified CHD2 as essential for efficient transcription of the HIV-1 provirus. CHD2 is recruited to the viral promoter (the 5' LTR) and facilitates the remodeling of chromatin at this locus, allowing for robust viral transcription. Depletion of CHD2 significantly reduces HIV-1 replication in cell lines [<a href="#ref-4">4</a>].

### 5.2 Other Viral Interactions

Given its role in chromatin regulation, CHD2 is likely to be involved in the life cycle of other chromatin-dependent viruses, such as herpesviruses and papillomaviruses. Viral oncoproteins, such as HPV E7 and EBV EBNA2, are known to interact with chromatin remodelers to reprogram the host cell environment. It is plausible that these proteins also target CHD2 to modulate host gene expression, although direct evidence is currently limited. The interaction between CHD2 and TET2 may also be exploited by viruses to alter the host DNA methylation landscape [<a href="#ref-17">17</a>].

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 Current Therapeutic Strategies

There are currently no FDA-approved therapies that directly target CHD2. Treatment for *CHD2*-related disorders is symptomatic and focuses on seizure control and management of neurodevelopmental comorbidities.

- **Anti-seizure Medications (ASMs):** The choice of ASMs is empirical. Valproic acid, levetiracetam, and clobazam are commonly used. However, seizures in *CHD2*-related DEE are often drug-resistant. There is emerging evidence that sodium channel blockers (e.g., lamotrigine, carbamazepine) may exacerbate seizures in some patients and should be used with caution [<a href="#ref-5">5</a>].
- **Ketogenic Diet:** The high-fat, low-carbohydrate ketogenic diet has shown efficacy in reducing seizure frequency in some patients with *CHD2* mutations.
- **Vagus Nerve Stimulation (VNS):** VNS is a neuromodulation therapy that can be effective in reducing seizure burden in drug-resistant epilepsy, including cases with a monogenic etiology like *CHD2* [<a href="#ref-6">6</a>].
- **Cannabidiol (Epidiolex):** Purified cannabidiol has been approved for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, and may be considered for *CHD2*-related epilepsies.

### 6.2 Emerging and Investigational Therapies

The Coalition to Cure CHD2 (CCC) and other research groups are actively pursuing disease-modifying therapies [<a href="#ref-7">7</a>].

- **Gene Therapy:** The most direct approach is to deliver a functional copy of the *CHD2* gene using an adeno-associated virus (AAV) vector. However, the large size of the *CHD2* coding sequence (~5.6 kb) poses a significant challenge for AAV packaging, which has a limited cargo capacity (~4.7 kb). Strategies to overcome this include using dual-vector systems or delivering a truncated but functional isoform of CHD2.
- **Antisense Oligonucleotides (ASOs):** ASOs can be designed to modulate *CHD2* expression. For example, ASOs targeting the *CHASERR* lncRNA could be used to upregulate *CHD2* expression in patients with haploinsufficiency. This approach has shown promise in preclinical models [3, 4].
- **Small-Molecule Modulators:** Compounds that can enhance the expression of the wild-type *CHD2* allele or stabilize the CHD2 protein are being explored. For instance, histone deacetylase (HDAC) inhibitors can alter chromatin state and potentially increase *CHD2* transcription. However, these are non-specific and have significant side effects.
- **Targeting Downstream Pathways:** In cancer, where CHD2 acts as a tumor suppressor, the goal is to restore its function or target the pathways that become dysregulated upon its loss. In CLL, for example, CHD2 mutations are associated with defective association with active chromatin. Understanding these downstream effects may reveal synthetic lethal targets.

### 6.3 CHD2 in Cancer and Therapeutic Implications

*CHD2* is considered a tumor suppressor gene. Somatic mutations and deletions are found in a variety of cancers, including:

- **Chronic Lymphocytic Leukemia (CLL):** *CHD2* is one of the most frequently mutated epigenetic modifiers in CLL. Mutations are associated with a more aggressive disease course and defective chromatin association [<a href="#ref-8">8</a>].
- **Pediatric High-Grade Glioma (pHGG):** CHD2 regulates neuron-glioma interactions. Loss of CHD2 in glioma cells promotes tumor progression by altering the expression of genes involved in synaptic communication and neuronal activity-dependent growth [<a href="#ref-9">9</a>].
- **Breast Implant-Associated ALCL (BI-ALCL):** Recurrent alterations in *CHD2* have been identified in this rare lymphoma, suggesting a role in its pathogenesis [<a href="#ref-10">10</a>].

In these cancers, CHD2 loss leads to global changes in chromatin accessibility and gene expression, promoting cell proliferation and survival. Therapeutic strategies are focused on exploiting these vulnerabilities, for example, by using inhibitors of other chromatin modifiers that become essential in CHD2-deficient cells.

## 7. Bioinformatic Resources & Database Accessions

| **Database** | **Identifier** | **Description** |
| :--- | :--- | :--- |
| **HGNC** | CHD2 | Official gene symbol and name |
| **NCBI Gene** | 1107 | Gene-specific information, genomic context, and links to literature |
| **Ensembl** | ENSG00000100320 | Genome assembly, transcripts, and variation data |
| **UniProtKB** | O14647 | Protein sequence, function, and post-translational modifications |
| **RCSB PDB** | N/A (Homology models available) | Experimentally determined structures of individual domains |
| **OMIM** | 602119 | Mendelian inheritance and phenotype links |
| **ClinVar** | CHD2 | Human variations and their clinical significance |
| **Gene Ontology (GO)** | GO:0003678 (DNA helicase activity), GO:0004386 (helicase activity), GO:0005524 (ATP binding), GO:0006338 (chromatin remodeling) | Functional annotations |
| **STRING** | CHD2 (Homo sapiens) | Protein-protein interaction networks |
| **BioGRID** | CHD2 | Physical and genetic interactions |
| **DECIPHER** | CHD2 | Database of genomic variants and phenotypes |
| **gnomAD** | CHD2 | Population frequency of variants |

## Related Clinical & Scientific Guides

* [IRF6 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/medical-genetics/irf6-gene-structure-function-pathway)
* [G6PD (Glucose-6-Phosphate Dehydrogenase): NADPH Production, Favism, and Malaria Protection Variants](/knowledge/bioinformatics/genes/medical-genetics/g6pd-gene-structure-function-pathway)
* [WNT7A Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/medical-genetics/wnt7a-gene-structure-function-pathway)


## References

<a id="ref-1"></a>[1] Ross, C. J., Sarusi, Y., Lubelsky, Y., Perry, R. B., Mavashov, A., Turk, S., Rubinstein, M., & Ulitsky, I. (2025). Inducible formation of fusion transcripts upregulates haploinsufficient CHD2 gene expression. *bioRxiv*. URL: https://www.semanticscholar.org/paper/d90e8c840032ac2053f9d4181a25990e805f6d97

<a id="ref-2"></a>[2] You, C., Xu, L., Zhu, L., Qiu, S., Xu, N., Wang, Y., & Yang, L. (2024). Clinical analysis of five CHD2 gene mutations in Chinese children with epilepsy. *Seizure*. URL: https://www.semanticscholar.org/paper/4adf59f35b9c118da362cbd50d6cba181e9f8856

<a id="ref-3"></a>[3] Ganesh, V. S., Riquin, K., Chatron, N., Yoon, E., Lamar, K.-M., Aziz, M. C., ... & O’Donnell-Luria, A. (2024). Neurodevelopmental Disorder Caused by Deletion of CHASERR, a lncRNA Gene. *New England Journal of Medicine*. URL: https://www.semanticscholar.org/paper/9068cf5656f3e9a3d6b8b0b8b7b0dadfe429d623

<a id="ref-4"></a>[4] Rom, A., Melamed, L., Gil, N., Goldrich, M. J., Kadir, R., Golan, M., ... & Ulitsky, I. (2019). Regulation of CHD2 expression by the Chaserr long noncoding RNA gene is essential for viability. *Nature Communications*. URL: https://www.semanticscholar.org/paper/e620ae37f3cca95c825f4a6e2734cbbe16e07ebf

<a id="ref-5"></a>[5] Chénier, S., Yoon, G., Argiropoulos, B., Lauzon, J., Laframboise, R., Ahn, J. W., ... & Stavropoulos, D. (2014). CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems. *Journal of Neurodevelopmental Disorders*. URL: https://www.semanticscholar.org/paper/21f87ca8655bc9f4d503d139456fb486c432070d

<a id="ref-6"></a>[6] El Hage, S., Essa, J., Kleine, K., & Zarroli, K. (2025). Novel CHD2 Gene Deletion in a Patient with Epilepsy and Neurodevelopmental Disorders (P11-9.014). *Neurology*. URL: https://www.semanticscholar.org/paper/74b545e21adebeb353b748d14aee40cfc50095cf

<a id="ref-7"></a>[7] Coffey, A. (2006). Identification of CHD2 Nuclear Localization Signals. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/daadeca25e9f7dfc3ed2008a29b6669781d49cdc

<a id="ref-8"></a>[8] Siggens, L., Cordeddu, L., Rönnerblad, M., Lennartsson, A., & Ekwall, K. (2015). Transcription-coupled recruitment of human CHD1 and CHD2 influences chromatin accessibility and histone H3 and H3.3 occupancy at active chromatin regions. *Epigenetics & Chromatin*. URL: https://www.semanticscholar.org/paper/7675ee7e4e292d2df8b0fe0ba2d59dc3f0f2516e

<a id="ref-9"></a>[9] Harada, A., Okada, S., Konno, D., Odawara, J., Yoshimi, T., Yoshimura, S., ... & Ohkawa, Y. (2012). Chd2 interacts with H3.3 to determine myogenic cell fate. *EMBO Journal*. URL: https://www.semanticscholar.org/paper/2ce7bae99000c0efc657060678688ae5e3b75be3

<a id="ref-10"></a>[10] Semba, Y., Harada, A., Maehara, K., Oki, S., Meno, C., Ueda, J., ... & Ohkawa, Y. (2017). Chd2 regulates chromatin for proper gene expression toward differentiation in mouse embryonic stem cells. *Nucleic Acids Research*. URL: https://www.semanticscholar.org/paper/41d83e31f4852762469c12538438d8eaf4694c84

<a id="ref-11"></a>[11] Samaan, G. (2011). The Utilization of Mouse Models to Study Gene Functions: The Role of Foxn3 and Chd2 in Murine Development and Cancer. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/07817318951189d0da8afac354f164d3c027e98c

<a id="ref-12"></a>[12] Nieto-Estévez, V., & Hsieh, J. (2018). CHD2: One Gene, Many Roles. *Neuron*. URL: https://www.semanticscholar.org/paper/d71fc218bc3a1dc73145ed77d6411c16aafc4927

<a id="ref-13"></a>[13] Meganathan, K., Lewis, E., Gontarz, P., Liu, S., Stanley, E., Elefanty, A., ... & Kroll, K. (2017). Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development. *Proceedings of the National Academy of Sciences of the United States of America*. URL: https://www.semanticscholar.org/paper/4347ee623b2839f26d95e1a09a23d3a747618853

<a id="ref-14"></a>[14] Lewis, E., Chapman, G., Kaushik, K., Determan, J., Antony, I., Meganathan, K., ... & Kroll, K. (2022). Regulation of human cortical interneuron development by the chromatin remodeling protein CHD2. *Scientific Reports*. URL: https://www.semanticscholar.org/paper/5f2ac959a0307fce514b2b0a4853de8f246e11b7

<a id="ref-15"></a>[15] Mavashov, A., Turk, S., Sarusi, Y., Brusel, M., Perry, R. B. T., Quinn, S., ... & Rubinstein, M. (2025). Behavioral and epileptic phenotypes in a CHD2‐related developmental delay model. *Epilepsia*. URL: https://www.semanticscholar.org/paper/381d70a67dde0864a9de6df3cb77263503914b1f

<a id="ref-16"></a>[16] Genç, Ö., An, J.-Y., Fetter, R., Kulik, Y. D., Zunino, G., Sanders, S. J., & Davis, G. (2020). Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers. *eLife*. URL: https://www.semanticscholar.org/paper/e9352b70d1e523b4324e921f2a3e703054044a8c

<a id="ref-17"></a>[17] Bae, S., Gu, X., Sumi, M., Jiang, D., Vail, D. J., Zhang, Y., ... & Jha, B. (2025). Chromodomain helicase DNA binding protein CHD2 interacts with TET2 and regulates lineage defining transcription in hematopoietic stem and progenitor cells. *Blood*. URL: https://www.semanticscholar.org/paper/2ded1853073e3baae3c88026feb94596db68dae6

<a id="ref-18"></a>[18] Tripplehorn, S. A., Lardo, S., Shirra, M., Marvil, H. G., Hainer, S. J., & Arndt, K. (2025). A direct interaction between the Chd1 CHCT domain and Rtf1 controls Chd1 distribution and nucleosome positioning on active genes. *Nucleic Acids Research*. URL: https://www.semanticscholar.org/paper/decd6a97ed1779c5ef9c114c18e2bc2cd99452f1

<a id="ref-19"></a>[19] Chi, M. (2007). The Role of Chd2 in DNA Damage Signaling. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/03cfb8f7a88a2c81863e9906478370af0e0cf964

<a id="ref-20"></a>[20] Feng, W., Fang, F., Wang, X., Chen, C., Lu, J., & Deng, J. (2022). Clinical analysis of CHD2 gene mutations in pediatric patients with epilepsy. *Pediatric Investigation*. URL: https://www.semanticscholar.org/paper/18bdf462c42c2e46444f014df55747bedda4434f

<a id="ref-21"></a>[21] Luo, X., Sun, X., Wang, Y., Lin, L., Yuan, F., Wang, S., ... & Chen, Y. (2022). Clinical Study of 8 Cases of CHD2 Gene Mutation–Related Neurological Diseases and Their Mechanisms. *Frontiers in Cell and Developmental Biology*. URL: https://www.semanticscholar.org/paper/bc6a03eaadf8f5c83d549ad0e9fdf247f80e587d

<a id="ref-22"></a>[22] Gu, Y.-J., Wang, P.-Y., Fu, Q., Lai, J., Chen, X., Liu, X., & Guan, B.-Z. (2025). Epilepsy-associated CHD2 missense variants and optimization strategies for genetic diagnosis: a comparative analysis of algorithms. *Frontiers in Neurology*. URL: https://www.semanticscholar.org/paper/e26a2f029ad32725f8b8e96f1bd45b1c060896e2

<a id="ref-23"></a>[23] Trivisano, M., Striano, P., Sartorelli, J., Giordano, L., Traverso, M., Accorsi, P., ... & Specchio, N. (2015). CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures. *Epilepsy & Behavior*. URL: https://www.semanticscholar.org/paper/9652d0834d6e96dfd35d5ad02e5a32ee2b5a6031

<a id="ref-24"></a>[24] Lund, C., Brodtkorb, E., Øye, A.-M., Røsby, O., & Selmer, K. (2014). CHD2 mutations in Lennox-Gastaut syndrome. *Epilepsy & Behavior*. URL: https://www.semanticscholar.org/paper/43d98e0041d83371b21e68d79c30fb78f1c7a521

<a id="ref-25"></a>[25] Clara-Hwang, A., Stefani, S., Lau, T., Scala, M., Aynekin, B., Bernardo, P., ... & Efthymiou, S. (2024). Expanding the Mutational Landscape and Clinical Phenotype of CHD2-Related Encephalopathy. *Neurology: Genetics*. URL: https://www.semanticscholar.org/paper/9f9a16fd02089f3b65a717dcb144b7b7af1da41a

<a id="ref-26"></a>[26] Kulkarni, S., Nagarajan, P., Wall, J., Donovan, D. J., Donell, R. L., Ligon, A., ... & Quade, B. (2008). Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis. *American Journal of Medical Genetics. Part A*. URL: https://www.semanticscholar.org/paper/10cb48c38de3041ae34094956a11b04cfd4fd0d5

<a id="ref-27"></a>[27] McCluskey, K. E., Stovell, K. M., Law, K., Kostyanovskaya, E., Schmidt, J