Chd2-Related Neurodevelopmental Disorders

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2021-01-18

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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.

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). 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 ¹	Test Method	Proportion of Probands with a CHD2 Pathogenic Variant ² Detectable by This Method
CHD2	Sequence analysis ³	24/32 (75%)
	Deletion/duplication analysis ⁴ (genomic approach)	8/32 (25%) ⁵
	Gene-targeted deletion/duplication analysis ⁶	Unknown ⁷

1.: See Table A. Genes and Databases for chromosome locus and protein.
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.