CHD2-Related Neurodevelopmental Disorders

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 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.

Diagnosis/testing.

The diagnosis of a CHD2-related neurodevelopmental disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in CHD2 identified by 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 anti-seizure medications exist, as the best regimen for CHD2-related neurodevelopmental disorders is not yet established. Most Individuals remain refractory to treatment and require multiple anti-seizure medications. Support services for those with developmental delay, intellectual disability, and/or associated psychiatric/behavioral disorders.

Surveillance: At each visit assess for new seizures or change in seizures; evaluate developmental progress and educational needs; behavioral assessment for anxiety, attention, and aggressive or self-injurious behavior; assess family need for social work support and care coordination.

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

Genetic counseling.

CHD2-related neurodevelopmental disorders are autosomal dominant disorders typically caused by a de novo pathogenic variant. If the CHD2 pathogenic variant identified in the proband is not identified in either parent, the risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism. Once the CHD2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

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

• Early-onset developmental and epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity [Scheffer et al 2017]), particularly those with:
  • Seizure onset between ages six months and four years
  • Drop attacks and 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). However, 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 suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in CHD2 identified by molecular genetic testing (see Table 1).

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) or genomic testing (chromosomal microarray analysis [CMA] or comprehensive genomic sequencing).

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the phenotypes of many genetic epileptic encephalopathies overlap, most children with CHD2-related neurodevelopmental disorder with epilepsy are diagnosed by the following recommended testing (a multigene panel or CMA) or testing to be considered (comprehensive genomic sequencing).

Testing to Consider

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an intellectual disability multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability whereas some multigene panels may not.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Resolution of variants of uncertain significance (VUS). Many disorders that perturb regulators of epigenetic processes result in a very specific DNA methylation pattern that is common to all affected individuals with pathogenic variants in that gene [Aref-Eshghi et al 2020]. Identification of an "episignature" characteristic of CHD2-related neurodevelopmental disorders can be used to resolve VUS in CHD2.

Table 1.

Molecular Genetic Testing Used in CHD2-Related Neurodevelopmental Disorders

Clinical Description

To date 139 individuals with a CHD2-related neurodevelopmental disorder have been reported [Carvill et al 2013, Suls et al 2013, O'Roak et al 2014, Deciphering Developmental Disorders Study Group 2015, Thomas et al 2015, Heyne et al 2018, Ko et al 2018, Truty et al 2019, Chen et al 2020].

A systematic single study of individuals with CHD2-related neurodevelopmental disorders has not yet been published. To date, epilepsy is a consistent feature across the phenotypic spectrum of CHD2-related neurodevelopmental disorders and most individuals reported have presented with developmental and epileptic encephalopathy. However, as genetic testing becomes more widely available and less targeted (i.e., more genes are included in multigene panels) the phenotypic spectrum is evolving.

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

Table 2.

Select Features of CHD2-Related Neurodevelopmental Disorders

Seizures. The age of onset ranges from six months to 12 years; median seizure onset is 30 months (2.5 years).

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

Although CHD2-related epilepsy has been compared to Dravet syndrome in at least one study, febrile seizures, which are characteristic of Dravet syndrome, have only been reported in 11 individuals with CHD2 variants [Carvill et al 2013, Suls et al 2013, Thomas et al 2015, Petersen et al 2018, Chen et al 2020].

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 a total of 80% (20/25) of individuals where it was specifically queried. A small number of individuals 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, a particularly photosensitive epilepsy syndrome [Galizia et al 2015].

Seizures are often refractory to currently available anti-seizure medications (ASMs). Only 13 of 33 affected individuals have been reported to be seizure free on ASM treatment for two to five years (see Management) [Thomas et al 2015, Chen et al 2020].

Psychomotor development prior to seizures can be delayed (n=20) but is often not reported and this feature requires further evaluation. When specifically reported in the literature, intellectual disability ranges from mild (in 7/15 individuals) to severe (8/15 individuals).

Behavior and neuropsychiatric phenotypes. Autism spectrum disorder or autistic features have been reported in 56% (39/70) of individuals. Challenging behaviors, most often aggression, have been described, with three requiring medical treatment with risperidone [Thomas et al 2015]. Attention-deficit/hyperactivity disorder and psychosis have also been reported in a small number of individuals. There is also a single individual diagnosed with schizophrenia [Poisson et al 2020]. It is currently unclear to what extent a specific behavior phenotype is part of the phenotypic spectrum and this requires further investigation for management.

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.

Penetrance

Penetrance for CHD2-related neurodevelopmental disorders is unknown but assumed to be complete. There are a small number of instances where the CHD2 variant is inherited from a presumably unaffected parent or a parent with a milder phenotype [Petersen et al 2018, Chen et al 2020]. In such instances it is important to evaluate the parent for somatic mosaicism.

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 developmental and epileptic encephalopathies [Allen et al 2013, Carvill et al 2013]. In another report of nearly 10,000 individuals referred for genetic testing using a comprehensive epilepsy panel, 0.25% of individuals has a CHD2 pathogenic variant identified [Truty et al 2019]. In individuals with a neurodevelopmental disorder that included epilepsy, CHD2 was the fourth most highly implicated gene [Heyne et al 2018].

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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a CHD2-related neurodevelopmental disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with CHD2-Related Neurodevelopmental Disorders

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with CHD2-Related Neurodevelopmental Disorders

Surveillance

Table 5.

Recommended Surveillance for Individuals with CHD2-Related Neurodevelopmental Disorders

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 affected individuals 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 EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

CHD2-related neurodevelopmental disorders are autosomal dominant disorders typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Almost all individuals diagnosed with a CHD2-related neurodevelopmental disorder have the disorder as the result of a de novo pathogenic variant.
• In rare families, individuals diagnosed with a CHD2-related neurodevelopmental disorder have the disorder as the result of a CHD2 pathogenic variant inherited from a parent. For example:
  • A child with a severe presentation of CHD2-related neurodevelopmental disorder inherited a CHD2 pathogenic variant from her heterozygous, less severely affected mother [Petersen et al 2018]. Her mother had seizures as a child (well controlled with anti-seizure medications) and neuropsychiatric features (including bipolar disorder, ADHD, language delays, and dyslexia) but no learning difficulties throughout childhood [Petersen et al 2018].
  • A child with epilepsy and myoclonic seizures inherited a splice variant from his apparently unaffected heterozygous father [Chen et al 2020].
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Presumed parental germline mosaicism was reported in a family with unaffected parents and sib recurrence [Lebrun et al 2017]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of an individual diagnosed with a CHD2-related neurodevelopmental disorder may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the proband has a known CHD2 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Lebrun et al 2017].
• If the parents have not been tested for the CHD2 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a CHD2-related neurodevelopmental disorder because of the possibility of parental germline mosaicism [Lebrun et al 2017, Myers et al 2018].

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.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CHD2 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 of having a child with a CHD2-related neurodevelopmental disorder.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular 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 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].

The overwhelming majority of CHD2 pathogenic variants lead to either truncation of the protein or loss of gene expression by whole-gene deletion. The pathogenic missense variants cluster in the functional domains and likely impair the ability of CHD2 to either bind to DNA targets and/or remodel chromatin. Collectively this suggests that CHD2-related neurodevelopmental disorders result from haploinsufficiency of CHD2.

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. The function of CHD2 in the human brain is not known. Complete CHD2 loss in a human stem cell model resulted in defects in the development of inhibitory interneurons and altered expression of genes important in neurotransmission [Meganathan et al 2017]. A heterozygous Chd2 loss mouse showed deficits in neuronal development including reduced number of both excitatory and inhibitory neurons and severe impairments in long-term memory. These animals did not exhibit seizures [Kim et al 2018].

Mechanism of disease causation. The majority of pathogenic variants lead to truncation of CHD2. The few reported de novo missense pathogenic variants occur in the highly conserved DNA-binding or 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.

Author Notes

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

Mefford Laboratory
St Jude Children’s Research Hospital
Center for Pediatric Neurological Disease Research
Department of Cell & Molecular Biology
262 Danny Thomas Place, Mail Stop 340
Memphis, TN 38105-3678

Carvill Laboratory
Northwestern University
303 E Chicago, Ward 9-183
Chicago, IL 60611
gemma.carvill@northwestern.edu
312-503-6187

Author History

Gemma Carvill, PhD (2015-present)
Ingo Helbig, MD; Children's Hospital of Philadelphia (2015-2021)
Heather Mefford, MD, PhD (2015-present)

Revision History

• 21 January 2021 (sw) Comprehensive update posted live
• 10 December 2015 (bp) Review posted live
• 14 May 2015 (hm/gc) Original submission

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