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CHD2-Related Neurodevelopmental Disorders

, PhD, , MD, and , MD, PhD.

Author Information

Initial Posting: .

Estimated reading time: 16 minutes

Summary

Clinical characteristics.

CHD2-related neurodevelopmental disorders are characterized by early-onset epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity). Seizure onset is typically between ages six months and four years. Seizure types typically include drop attacks, myoclonus, and a rapid onset of multiple seizure types associated with generalized spike-wave on EEG, atonic-myoclonic-absence seizures, and clinical photosensitivity. Intellectual disability and/or autism spectrum disorders are common. To date only 32 individuals with a CHD2-related neurodevelopmental disorder have been reported; thus, better understanding of the phenotypic spectrum of CHD2-related neurodevelopmental disorders is likely to evolve over time.

Diagnosis/testing.

The diagnosis of a CHD2-related neurodevelopmental disorder is established in a proband with a heterozygous CHD2 single-nucleotide pathogenic variant, small indel (insertion/deletion) pathogenic variant, or a partial- or whole-gene deletion detected on molecular genetic testing.

Management.

Treatment of manifestations: Seizures should be managed by an experienced pediatric neurologist. At this time, no specific guidelines regarding choice of specific antiepileptic drugs (AEDs) exist, as the best AED regimen for CHD2-related neurodevelopmental disorders is not yet established. Most patients remain refractory to treatment and require multiple AEDs.

Agents/circumstances to avoid: Because clinical photosensitivity may result in injuries due to the consequences of induced seizures, it is recommended that stimuli which may provoke seizures (e.g., intensely flickering lights) be avoided.

Genetic counseling.

CHD2-related neurodevelopmental disorders are inherited in an autosomal dominant manner. To date, all CHD2-related neurodevelopmental disorders have resulted from a de novo pathogenic variant (i.e., no familial occurrences are known). However, because of the possibility of germline mosaicism in a parent, the risk of recurrence is presumed to be greater than in the general population. Prenatal testing for pregnancies presumed to be at increased risk is possible.

GeneReview Scope

CHD2-Related Neurodevelopmental Disorders: Included Phenotypes 1
  • Developmental delay/intellectual disability
  • Epileptic encephalopathy
  • Autism spectrum disorders
1.

For other genetic causes of these phenotypes, see Differential Diagnosis.

Diagnosis

Suggestive Findings

CHD2-related neurodevelopmental disorders should be suspected in individuals with the following:

  • Early-onset epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity [Berg et al 2010]), particularly those with:
    • Seizure onset between ages six months and four years
    • Drop attacks and a rapid onset of multiple seizure types associated with generalized spike-wave on EEG
    • Atonic-myoclonic-absence seizures (see Clinical Description)
    • Clinical photosensitivity
      Note: Photic stimulation during an EEG may be a helpful diagnostic modality even though not all individuals with a CHD2-related neurodevelopmental disorder and clinical photosensitivity show an EEG response to photic stimulation. Nonetheless, the possible increased risk for photic-induced seizures in individuals with this disorder should be taken into account when obtaining an EEG with photic stimulation.
  • Intellectual disability and/or autism spectrum disorders, particularly when epilepsy is also present

Establishing the Diagnosis

The diagnosis of a CHD2-related neurodevelopmental disorder is established in a proband with a heterozygous CHD2 single-nucleotide pathogenic variant, small indel (insertion/deletion) pathogenic variant (Figure 1) or a partial- or whole-gene deletion detected on molecular genetic testing (Table 1).

Figure 1. . Distribution of single-nucleotide and small indel pathogenic variants in CHD2 in individuals with epileptic encephalopathy (top panel) and intellectual disability (ID) and autism spectrum disorder (ASD) (bottom panel).

Figure 1.

Distribution of single-nucleotide and small indel pathogenic variants in CHD2 in individuals with epileptic encephalopathy (top panel) and intellectual disability (ID) and autism spectrum disorder (ASD) (bottom panel). Vertical lines show the position (more...)

Molecular genetic testing approaches can include use of a multigene panel, chromosome microarray analysis (CMA), and more comprehensive genomic testing:

  • A multigene panel that includes CHD2 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Chromosome microarray analysis (CMA) – if not already performed as part of the diagnostic work up – may be performed to detect genome-wide deletions/duplications (including CHD2).
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes CHD2) fails to confirm a diagnosis in an individual with features of CHD2-related neurodevelopmental disorders. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in CHD2-Related Neurodevelopmental Disorders

Gene 1Test MethodProportion of Probands with a CHD2 Pathogenic Variant 2 Detectable by This Method
CHD2Sequence analysis 324/32 (75%)
Deletion/duplication analysis 4 (genomic approach)8/32 (25%) 5
Gene-targeted deletion/duplication analysis 6Unknown 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Deletion/duplication analysis (genomic approach) detects deletion of 15q26 using a chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

Individuals with features of CHD2-related disorders who have deletions encompassing CHD2 (with or without deletion of RGMA) have been reported [Dhamija et al 2011, Capelli et al 2012, Chénier et al 2014, Courage et al 2014, Pinto et al 2014].

6.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7.

No intragenic CHD2 multiexon deletions or duplications have been reported.

Clinical Characteristics

Clinical Description

To date 32 individuals with a CHD2-related neurodevelopmental disorder have been reported [Capelli et al 2012, Neale et al 2012, Rauch et al 2012, Lund et al 2013, Chénier et al 2014, Hamdan et al 2014, Lund et al 2014, O'Roak et al 2014, Pinto et al 2014, Deciphering Developmental Disorders Study Group 2015, Trivisano et al 2015].

Detailed clinical information is available for 16 of the 32 [Allen et al 2013, Suls et al 2013, Lund et al 2014, Thomas et al 2015, Trivisano et al 2015]. While epilepsy is a consistent feature across the phenotypic spectrum of CHD2-related neurodevelopmental disorders, it is likely that better understanding of the phenotypic spectrum will evolve as more affected individuals are identified.

The most common clinical features of these individuals are described below.

Seizures. The age of onset ranges from six months to four years.

Seizure onset, which is explosive in many children, is characterized by multiple, daily myoclonic and absence seizures.

Febrile seizures are rarely the first seizure type observed (4/16 children) [Allen et al 2013, Suls et al 2013, Lund et al 2014, Thomas et al 2015, Trivisano et al 2015].

A classic seizure type termed "atonic-myoclonic-absence seizure," a progressive seizure pattern comprising an abrupt head nod and atonia followed by a myoclonic absence phase and progression to a "ratchet-like" tonic abduction of the upper limbs, was observed in video footage of three children aged two to seven years. Seizures were brief (2-8 seconds) and awareness rapidly returned [Thomas et al 2015]. Many of the components of this seizure pattern have been described in other affected individuals; thus, future video monitoring and video-EEG monitoring will be important in determining if this seizure pattern is a hallmark of CHD2-related neurodevelopmental disorders.

Clinical photosensitivity (i.e., seizures triggered by photic stimulation) is a distinguishing feature reported in nine of 12 individuals. Seven of the nine could self-induce seizures, suggesting an unusually strong degree of photosensitivity. In contrast, a photoparoxysmal response (an epileptiform EEG response to intermittent photic stimulation) has only been recorded in two affected individuals [Lund et al 2014, Thomas et al 2015, Trivisano et al 2015]. Of note, some individuals with a CHD2 pathogenic variant have a diagnosis of eyelid myoclonia with absences (EMA), a particularly photosensitive epilepsy syndrome [Galizia et al 2015].

Seizures are generally refractory to currently available antiepileptic drugs (AEDs). Only four of 16 affected individuals have been reported to be seizure free on AED treatment for two to five years (see Management).

Psychomotor development prior to seizure onset is frequently delayed (11/16 children). When specifically reported in the literature, intellectual disability ranges from mild (7/15) to severe (8/15).

Behavior phenotypes. Autism spectrum disorder (ASD) or autistic features have been reported in six of 15 affected individuals. Challenging behaviors, most often aggression, were described in eight of 11 individuals, with three requiring medical treatment with risperidone. It is currently unclear to what extent a specific behavior phenotype is part of the phenotypic spectrum.

Neuroimaging. In some affected individuals MRI has shown atrophy that tends to be more posterior and can be progressive. In those with ataxia, cerebellar atrophy was more pronounced [Suls et al 2013, Thomas et al 2015].

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been observed between the location/nature of the pathogenic variant and clinical outcome (Figure 1); however, the number of reported individuals with a CHD2-related neurodevelopmental disorder is still relatively small and patterns may emerge as more affected individuals are identified.

A cluster of truncating pathogenic variants in the C terminus has been reported in individuals with epileptic encephalopathy, intellectual disability (ID), and/or autism spectrum disorders (ASD). Of note, the same recurrent pathogenic variant, p.Arg1637Ter, has been identified in an individual with ASD without seizures and in an individual with ID and a seizure disorder described as "genetic generalized epilepsy" [O'Roak et al 2014; Carvill, unpublished], suggesting phenotypic variability even in individuals with the same pathogenic variant.

Penetrance

Penetrance for CHD2-related neurodevelopmental disorders is unknown but assumed to be complete.

Prevalence

The prevalence of CHD2-related neurodevelopmental disorders is not known.

A de novo CHD2 pathogenic variant was present in an estimated 1% of individuals included in cohorts with various epileptic encephalopathies [Allen et al 2013, Carvill et al 2013].

In each of four studies of exome-based sequencing of hundreds to thousands of individuals with neurodevelopmental disorders including intellectual disability and autism spectrum disorders, one to three individuals with a de novo CHD2 pathogenic variant were identified [Neale et al 2012, Rauch et al 2012, O'Roak et al 2014, Deciphering Developmental Disorders Study Group 2015].

Differential Diagnosis

Myoclonic absence epilepsy (MAE) (also known as Doose syndrome) was the original diagnosis in three of six individuals with a de novo CHD2 pathogenic variant [Carvill et al 2013]. In contrast to individuals with MAE, patients with a CHD2-related neurodevelopmental disorder generally have delayed development prior to seizure onset and often have clinical photosensitivity. Tonic seizures are also more frequently seen in children with CHD2 pathogenic variants. Although the etiology is unknown in the majority of individuals with MAE, a de novo pathogenic variant in SLC2A1 or SLC6A1 was found in up to 10% of individuals in some case series [Mullen et al 2011, Carvill et al 2015].

Lennox Gastaut syndrome (LGS) was the original diagnosis in three individuals with a de novo CHD2 pathogenic variant. LGS is an epileptic encephalopathy characterized by multiple types of seizures that are typically refractory to treatment, moderate to severe intellectual disability, and a slow spike and wave pattern on EEG. The genetic causes are heterogeneous: de novo pathogenic variants have been identified in numerous genes including STXBP1, CDKL5, GABRB3, SCN1A, and SCN2A [Allen et al 2013]. See STXBP1 Encephalopathy with Epilepsy.

Dravet syndrome, an infantile epileptic encephalopathy with onset before age 15 months, is characterized by hemiclonic or generalized seizures that are often triggered and prolonged by fever. Additional seizure types develop over time and psychomotor regression and intellectual disability are common. Over 75% of individuals with Dravet syndrome have a de novo SCN1A pathogenic variant [Marini et al 2011]. In contrast to the seizures of Dravet syndrome, the seizures of CHD2-related neurodevelopmental disorders are not commonly triggered by fever (4/15 cases) [Suls et al 2013, Thomas et al 2015, Trivisano et al 2015].

Intellectual disability with epilepsy. A total of four individuals with nonsyndromic intellectual disability and a de novo CHD2 pathogenic variant have been identified by large exome sequencing studies. Three of the four also had epilepsy [Rauch et al 2012, Hamdan et al 2014, Deciphering Developmental Disorders Study Group 2015].

Autism spectrum disorder (ASD). A de novo CHD2 pathogenic variant was identified in four individuals in a targeted study of approximately 3500 individuals with ASD and in one individual in an exome sequencing study of 175 individuals. All five had ASD and intellectual disability; three also had epilepsy [Neale et al 2012, O'Roak et al 2014].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a CHD2-related neurodevelopmental disorder, the following evaluations are recommended:

  • Neurologic examination including:
    • EEG, which may provide an assessment of the overall degree of epileptic encephalopathy and may lead to more focused use of antiepileptic drugs (AEDs);
    • MRI, which is initially important to differentiate the genetic epilepsy from a lesional epilepsy and may lead to intensified conservative treatment rather than presurgical work up.
  • Developmental assessment
  • Clinical genetics and/or child neurology consultation

Treatment of Manifestations

Seizures should be managed by an experienced pediatric neurologist.

At this time, no specific guidelines regarding choice of specific antiepileptic drugs (AEDs) exist, as the best AED regimen for CHD2-related neurodevelopmental disorders is not yet established. Most patients remain refractory to treatment and require multiple AEDs.

Although a ketogenic diet may be a treatment option, it was not effective in three patients [Thomas et al 2015].

For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Agents/Circumstances to Avoid

Because clinical photosensitivity may result in injuries due to the consequences of induced seizures, the following are recommended:

  • Avoid flickering lights that may provoke seizures.
  • Advise patients and families that exposure to intensely flickering lights may provoke seizures including eyelid myoclonias, absence seizures, and generalized tonic-clonic seizures. Of note, most televisions do not transmit in the frequency range that is particularly provocative.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CHD2-related neurodevelopmental disorders are inherited in an autosomal dominant manner. To date, all CHD2-related neurodevelopmental disorders have resulted from a de novo pathogenic variant (i.e., no familial occurrences are known).

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • To date, all affected individuals have had a de novo CHD2 pathogenic variant suggesting a low risk to sibs. However, because of the possibility of germline mosaicism in a parent, the risk is presumed to be greater than in the general population.

Offspring of a proband

  • Each child of an individual with a CHD2-related neurodevelopmental disorder has a 50% chance of inheriting the CHD2 pathogenic variant.
  • To date, individuals with a CHD2-related neurodevelopmental disorder are not known to reproduce; however, many are still children.

Other family members. The risk to other family members depends on the status of the proband's parents. To date, no parents have been affected.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CHD2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for a CHD2-related neurodevelopmental disorder are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society (AES)
  • Autism Society of America
    Publishes the "Advocate," an informative quarterly magazine
    4340 East-West Highway
    Suite 350
    Betheseda MD 20814
    Phone: 800-328-8476 (toll-free); 301-657-0881
  • Canadian Epilepsy Alliance
    Canada
    Phone: 1-866-EPILEPSY (1-866-374-5377)
  • Citizens United for Research in Epilepsy (CURE)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • Simons VIP Connect Registry
    An online community for individuals with genetic causes of autism. Simons VIP Connect is currently recruiting for a research study aimed to better understand the medical, cognitive and behavioral phenotype of individuals with certain CNV's and genes related to autism.An online community for individuals with genetic causes of autism. Simons VIP Connect is currently recruiting for a research study aimed to better understand the medical, cognitive and behavioral phenotype of individuals with certain CNV's and genes related to autism.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CHD2-Related Neurodevelopmental Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CHD2-Related Neurodevelopmental Disorders (View All in OMIM)

602119CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 2; CHD2
615369EPILEPTIC ENCEPHALOPATHY, CHILDHOOD-ONSET; EEOC

Molecular Genetic Pathogenesis

CHD2 encodes the chromodomain DNA helicase binding protein 2. CHD2 and additional members of this family of proteins are responsible for remodeling chromatin, which controls the three-dimensional architecture of the genome and gene expression.

The function of CHD2 in the human brain is not known; in mice, the ortholog Chd2 binds the transcription factor MyoD in muscle and promotes the expression of genes that promote myogenesis [Harada et al 2012]. Moreover, when Chd2 was depleted from mouse neuronal progenitor cells, the pool of progenitor cells was reduced, and cells differentiated prematurely into other neural lineages [Shen et al 2015]. Human CHD2 may have a similar function in the brain and control neuronal development and/or functioning.

The overwhelming majority of CHD2 pathogenic variants lead to either truncation of the protein or loss of gene expression by whole-gene deletion, suggesting that CHD2-related neurodevelopmental disorders result from CHD2 haploinsufficiency. Mouse and zebrafish models exhibit global abnormalities; however, only zebrafish knockdowns had a neurologic phenotype indicative of seizures [Marfella et al 2006, Marfella et al 2008, Suls et al 2013]. In contrast to these model systems, to date the majority of individuals with a CHD2 pathogenic variant have a brain-restricted phenotype, suggesting a unique role for CHD2 in the human brain.

Gene structure. The longest CHD2 transcript variant (NM_001271.3) consists of 39 exons and a processed mRNA transcript of 9374 bp sequence. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The majority of pathogenic variants result in protein truncation or whole- or partial-gene deletions; only four missense pathogenic variants in the highly conserved helicase domains have been described.

Table 2.

CHD2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.335C>Gp.Ser112TerNM_001271​.3
NP_001262​.3
c.361C>Tp.Arg121Ter
c.1396C>Tp.Arg466Ter
c.1450_1451insTp.Arg485SerfsTer19
c.1502+1G>A--
c.1642T>Cp.Trp548Arg
c.1808delAp.Thr604LeufsTer19
c.1942C>Tp.Pro648Ser
c.2468T>Cp.Leu823Pro
c.2567A>Gp.Asp856Gly
c.2725C>Tp.Gln909Ter
Not givenp.Glu966SerfsTer2
c.4233_4236delAGAAp.Glu1412GlyfsTer64
c.4256_4274del19p.Lys1419fsTer1421
c.4720delGp.Gly1575ValfsTer17
c.4173dupAp.Gln1392ThrfsTer17
Not givenp.Leu1591Terfs
Not givenp.Asn1600SerfsTer209
c.4909C>Tp.Arg1637Ter
Not givenp.Gln1641Ter
c.4930_4931delAGp.Arg1644LysfsTer22
Not givenp.Gly1651TrpfsTer16
c.4971G>Ap.Trp1657Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The gene is ubiquitously expressed in mouse and human [Marfella et al 2006]. CHD2 comprises 1828 amino acids and encodes a DNA-binding chromatin remodeler (Figure 1). The protein consists of two chromodomains and a putative DNA binding domain; these domains are known or hypothesized to bind DNA [Marfella & Imbalzano 2007, Liu et al 2015]. The ATP-helicase and DEDX-helicase domain are known in other family members to remodel chromatin using the energy of ATP hydrolysis [Marfella & Imbalzano 2007, Bouazoune & Kingston 2012].

Abnormal gene product. The majority of pathogenic variants lead to truncation of CHD2. The few reported de novo missense pathogenic variants (Figure 1) occur in the highly conserved helicase domains and likely hinder the ability of CHD2 to remodel chromatin. CHD2 pathogenic variants are likely all loss-of-function, resulting in CHD2-related neurodevelopmental disorders due to haploinsufficiency of CHD2.

References

Literature Cited

  • Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB, Han Y, Heinzen EL, Hitomi Y, Howell KB, Johnson MR, Kuzniecky R, Lowenstein DH, Lu YF, Madou MR, Marson AG, Mefford HC, Esmaeeli Nieh S, O'Brien TJ, Ottman R, Petrovski S, Poduri A, Ruzzo EK, Scheffer IE, Sherr EH, Yuskaitis CJ, Abou-Khalil B, Alldredge BK, Bautista JF, Boro A, Cascino GD, Consalvo D, Crumrine P, Devinsky O, Fiol M, Fountain NB, French J, Friedman D, Geller EB, Glynn S, Haut SR, Hayward J, Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, McGuire SM, Motika PV, Novotny EJ, Paolicchi JM, Parent JM, Park K, Shellhaas RA, Shih JJ, Singh R, Sirven J, Smith MC, Sullivan J, Lin Thio L, Venkat A, Vining EP, Von Allmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MR. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–21. [PMC free article: PMC3773011] [PubMed: 23934111]
  • Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, Moshé SL, Nordli D, Plouin P, Scheffer IE. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676–85. [PubMed: 20196795]
  • Bouazoune K, Kingston RE. Chromatin remodeling by the CHD7 protein is impaired by mutations that cause human developmental disorders. Proc Natl Acad Sci U S A. 2012;109:19238–43. [PMC free article: PMC3511097] [PubMed: 23134727]
  • Capelli LP, Krepischi AC, Gurgel-Giannetti J, Mendes MF, Rodrigues T, Varela MC, Koiffmann CP, Rosenberg C. Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency. Eur J Med Genet. 2012;55:132–4. [PubMed: 22178256]
  • Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Moller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45:825–30. [PMC free article: PMC3704157] [PubMed: 23708187]
  • Carvill GL, McMahon JM, Schneider A, Zemel M, Myers CT, Saykally J, Nguyen J, Robbiano A, Zara F, Specchio N, Mecarelli O, Smith RL, Leventer RJ, Møller RS, Nikanorova M, Dimova P, Jordanova A, Petrou S, Helbig I, Striano P, Weckhuysen S, Berkovic SF, Scheffer IE, Mefford HC, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet. 2015;96:808–15. [PMC free article: PMC4570550] [PubMed: 25865495]
  • Chénier S, Yoon G, Argiropoulos B, Lauzon J, Laframboise R, Ahn JW, Ogilvie CM, Lionel AC, Marshall CR, Vaags AK, Hashemi B, Boisvert K, Mathonnet G, Tihy F, So J, Scherer SW, Lemyre E, Stavropoulos DJ. CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems. J Neurodev Disord. 2014;6:9. [PMC free article: PMC4022362] [PubMed: 24834135]
  • Courage C, Houge G, Gallati S, Schjelderup J, Rieubland C. 15q26.1 microdeletion encompassing only CHD2 and RGMA in two adults with moderate intellectual disability, epilepsy and truncal obesity. Eur J Med Genet. 2014;57:520–3. [PubMed: 24932903]
  • Deciphering Developmental Disorders Study Group. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223–8. [PMC free article: PMC5955210] [PubMed: 25533962]
  • Dhamija R, Breningstall G, Wong-Kisiel L, Dolan M, Hirsch B, Wirrell E. Microdeletion of chromosome 15q26.1 in a child with intractable generalized epilepsy. Pediatr Neurol. 2011;45:60–2. [PubMed: 21723464]
  • Galizia EC, Myers CT, Leu C, de Kovel CGF, Afrikanova T, Cordero-Maldonado ML, Martins TG, Jacmin M, Drury S, Chinthapalli VK, Muhle H, Pendziwiat M, Sander T, Ruppert A-K, Moller RS, Thiele H, Krause R, Schubert J, Lehesjoki A-E, Nurnberg P, Lerche H, Palotie A, Coppola A, Striano S, Del Gaudio L, Boustred C, Schneider AL, Lench N, Jocic-Jakubi B, Covanis A, Capovilla G, Veggotti P, Piccioli M, Parisi P, Cantonetti L, Sadleir LG, Mullen SA, Berkovic SF, Stephani U, Helbig I, Crawford AD, Esguerra CV, Kasteleijn-Nolst Trenite DGA, Koeleman BPC, Mefford HC, Scheffer IE, Sisodiya SM. CHD2 variants are a risk factor for photosensitivity in epilepsy. Brain. 2015;138:1198–207. [PMC free article: PMC4407192] [PubMed: 25783594]
  • Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C, Patry L, Massicotte C, Ambalavanan A, Spiegelman D, Diallo O, Henrion E, Dionne-Laporte A, Fougerat A, Pshezhetsky AV, Venkateswaran S, Rouleau GA, Michaud JL. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014;10:e1004772. [PMC free article: PMC4214635] [PubMed: 25356899]
  • Harada A, Okada S, Konno D, Odawara J, Yoshimi T, Yoshimura S, Kumamaru H, Saiwai H, Tsubota T, Kurumizaka H, Akashi K, Tachibana T, Imbalzano AN, Ohkawa Y. Chd2 interacts with H3.3 to determine myogenic cell fate. Embo J. 2012;31:2994–3007. [PMC free article: PMC3395093] [PubMed: 22569126]
  • Liu JC, Ferreira CG, Yusufzai T. Human CHD2 Is a chromatin assembly ATPase regulated by its chromo- and DNA-binding domains. J Biol Chem. 2015;290:25–34. [PMC free article: PMC4281729] [PubMed: 25384982]
  • Lund C, Brodtkorb E, Oye AM, Rosby O, Selmer KK. CHD2 mutations in Lennox-Gastaut syndrome. Epilepsy Behav. 2014;33:18–21. [PubMed: 24614520]
  • Lund C, Brodtkorb E, Rosby O, Rodningen OK, Selmer KK. Copy number variants in adult patients with Lennox-Gastaut syndrome features. Epilepsy Res. 2013;105:110–7. [PubMed: 23415449]
  • Marfella CG, Imbalzano AN. The Chd family of chromatin remodelers. Mutat Res. 2007;618:30–40. [PMC free article: PMC1899158] [PubMed: 17350655]
  • Marfella CG, Henninger N, LeBlanc SE, Krishnan N, Garlick DS, Holzman LB, Imbalzano AN. A mutation in the mouse Chd2 chromatin remodeling enzyme results in a complex. Kidney Blood Press Res. 2008;31:421–32. [PMC free article: PMC2818461] [PubMed: 19142019]
  • Marfella CG, Ohkawa Y, Coles AH, Garlick DS, Jones SN, Imbalzano AN. Mutation of the SNF2 family member Chd2 affects mouse development and survival. J Cell Physiol. 2006;209:162–71. [PubMed: 16810678]
  • Marini C, Scheffer IE, Nabbout R, Suls A, De Jonghe P, Zara F, Guerrini R. The genetics of Dravet syndrome. Epilepsia. 2011;52:24–9. [PubMed: 21463275]
  • Mullen SA, Marini C, Suls A, Mei D, Della Giustina E, Buti D, Arsov T, Damiano J, Lawrence K, De Jonghe P, Berkovic SF, Scheffer IE, Guerrini R. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol. 2011;68:1152–5. [PubMed: 21555602]
  • Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH Jr, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242–5. [PMC free article: PMC3613847] [PubMed: 22495311]
  • O'Roak BJ, Stessman HA, Boyle EA, Witherspoon KT, Martin B, Lee C, Vives L, Baker C, Hiatt JB, Nickerson DA, Bernier R, Shendure J, Eichler EE. Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat Commun. 2014;5:5595. [PMC free article: PMC4249945] [PubMed: 25418537]
  • Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, Scherer SW. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94:677–94. [PMC free article: PMC4067558] [PubMed: 24768552]
  • Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Ropke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schrock E, Wieacker P, Riess O, Meitinger T, Reis A, Strom TM. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674–82. [PubMed: 23020937]
  • Shen T, Ji F, Yuan Z, Jiao J. CHD2 is required for embryonic neurogenesis in the developing cerebral cortex. Stem Cells. 2015;33:1794–806. [PubMed: 25786798]
  • Suls A, Jaehn JA, Kecskes A, Weber Y, Weckhuysen S, Craiu DC, Siekierska A, Djemie T, Afrikanova T, Gormley P, von Spiczak S, Kluger G, Iliescu CM, Talvik T, Talvik I, Meral C, Caglayan HS, Giraldez BG, Serratosa J, Lemke JR, Hoffman-Zacharska D, Szczepanik E, Barisic N, Komarek V, Hjalgrim H, Moller RS, Linnankivi T, Dimova P, Striano P, Zara F, Marini C, Guerrini R, Depienne C, Baulac S, Kuhlenbaumer G, Crawford AD, Lehesjoki AE, de Witte PA, Palotie A, Lerche H, Esguerra CV, De Jonghe P, Helbig I. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet. 2013;93:967–75. [PMC free article: PMC3824114] [PubMed: 24207121]
  • Thomas RH, Zhang LM, Carvill GL, Archer JS, Heavin SB, Mandelstam SA, Craiu D, Berkovic SF, Gill DS, Mefford HC, Scheffer IE. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology. 2015;84:951–8. [PMC free article: PMC4351660] [PubMed: 25672921]
  • Trivisano M, Striano P, Sartorelli J, Giordano L, Traverso M, Accorsi P, Cappelletti S, Claps DJ, Vigevano F, Zara F, Specchio N. CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures. Epilepsy Behav. 2015;51:53–6. [PubMed: 26262932]

Chapter Notes

Author Notes

The Epilepsiome: A knowledgebase for genes related to human epilepsies:
CHD2 – this is what you need to know in 2015

Mefford Laboratory
University of Washington
Department of Pediatrics
HSB RR309
1959 NE Pacific Street
Seattle, WA 98195
Phone: +1 206.543.4748

Revision History

  • 10 December 2015 (bp) Review posted live
  • 14 May 2015 (hm/gc) Original submission
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