Clinical characteristics.

CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is characterized by generalized overgrowth, developmental delay / intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, sleep disturbance, and gastrointestinal issues The most common findings are the development of macrocephaly (most often during infancy) and tall stature (most typically during puberty), which is often accompanied by ASD and/or DD/ID. Most, if not all, affected individuals have some degree of DD, most commonly speech and motor delays. When present, ID is most often in the mild-to-moderate range. Sleep disturbance is characterized by difficulty with both initiation (delayed sleep onset) and maintenance (frequent night awakenings) of sleep. The most common gastrointestinal issue is constipation with or without periods of diarrhea. Less common features are hypotonia (about 30% of affected individuals), seizures (10%-15%), dystonia (rare), and Chiari I malformation (rare).

Diagnosis/testing.

The diagnosis of CHD8-NDD is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in CHD8 by molecular genetic testing.

Management.

Treatment of manifestations: Sleep disturbance may be addressed through behavioral interventions and/or pharmacologic treatment; if Chiari I malformation is present, surgical treatment may be required; standard treatment for DD/ID, seizures, and bowel dysfunction.

Surveillance: At each visit: measurement of growth parameters (including head circumference); assessment of developmental progress and educational needs; monitor for signs and symptoms of anxiety, attention-deficit/hyperactivity disorder, and aggressive or self-injurious behavior; assess for new manifestations, such as seizures, changes in tone, and signs/symptoms of cerebrospinal fluid obstruction and/or spinal cord dysfunction; screen for signs/symptoms of sleep disturbance; monitor for constipation. Consider serial imaging for asymptomatic or minimally symptomatic Chiari I malformation as clinically indicated.

Genetic counseling.

CHD8-NDD is inherited in an autosomal dominant fashion. However, most probands reported to date whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CHD8 pathogenic variant. Each child of an individual with CHD8-NDD has a 50% chance of inheriting the CHD8 pathogenic variant. Once the CHD8 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

CHD8-NDD should be considered in individuals with the following clinical and family history findings.

Clinical findings

• Developmental delay (DD) and/or intellectual disability (ID) (typically in the mild-to-moderate range)
• Neuropsychiatric disorders, including autism spectrum disorder (ASD)
• Generalized overgrowth, including tall stature and macrocephaly
• Sleep disturbance
• Gastrointestinal problems, especially constipation

Family history. The majority of cases of CHD8-NDD are due to a de novo pathogenic variant, and most probands represent a simplex case (i.e., a single occurrence in a family). A minority of cases of CHD8-NDD are inherited in an autosomal dominant manner (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of CHD8-NDD is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in CHD8 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous CHD8 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with DD/ID and/or ASD with macrocephaly may include FMR1 analysis (molecular genetic testing for fragile X syndrome), chromosomal microarray analysis (CMA), multigene panels, and exome/genome sequencing. Note: Single-gene testing (sequence analysis of CHD8, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including CHD8) that may not be detected by sequencing.
• An ID, ASD, and/or overgrowth multigene panel that includes CHD8 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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.
• Further comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used. Genome sequencing may also be performed and yields results similar to an ID multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID, ASD, and/or overgrowth, 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.

Epigenetic signature analysis / methylation array. A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with CHD8-NDD [Aref-Eshghi et al 2020, Levy et al 2021]. Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1) suggestive findings of CHD8-NDD but in whom no pathogenic variant in CHD8 has been identified via sequence analysis or genomic testing; or (2) suggestive findings of CHD8-NDD and a CHD8 variant of uncertain clinical significance identified by molecular genetic testing. For an introduction to epigenetic signature analysis click here.

Clinical Description

To date, 115 individuals have been identified with a pathogenic heterozygous sequence variant in CHD8 for whom some phenotypic information is reported [Neale et al 2012, O'Roak et al 2012, Talkowski et al 2012, Bernier et al 2014, McCarthy et al 2014, Kimura et al 2016, Merner et al 2016, Stolerman et al 2016, Tatton-Brown et al 2017, Du et al 2018, Guo et al 2018, Wang et al 2018, Douzgou et al 2019, Ostrowski et al 2019, Alotaibi & Ramzan 2020, An et al 2020, Beighley et al 2020, Husson et al 2020, Tran et al 2020, Wu et al 2020, Coll-Tané et al 2021, Doummar et al 2021, Sadler et al 2021, Yamada et al 2021].

Of the 103 individuals for whom sex is known, 69 (67%) are male. This suggests a 2:1 male-to-female ratio, which is lower than the sex disparity previously reported [Douzgou et al 2019]. The reason for this sex difference is unknown, but it mirrors that of other neurodevelopmental disorders, indicating a possible ascertainment bias in who is referred for genetic testing.

The following description of the phenotypic features associated with CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is based on these reports.

Neurodevelopmental/neuropsychiatric issues

• Developmental delay (DD) in early childhood is common in individuals with CHD8-NDD. The majority are reported to have some degree of speech and/or motor delay, although the severity varies greatly. Developmental regression of social, speech, and/or motor skills in infancy and early childhood is reported in up to half of affected individuals [Bernier et al 2014, Merner et al 2016, Stolerman et al 2016, Wang et al 2018, An et al 2020, Wu et al 2020, Doummar et al 2021].
• Speech/language delays. While most individuals gain verbal speech, there are several case reports of individuals who are nonverbal in later childhood [Douzgou et al 2019, An et al 2020].
• Motor delays
  • When reported, delayed early motor milestones are present in 90% of affected individuals.
  • For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [Douzgou et al 2019].
  • Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [Stolerman et al 2016, Wang et al 2018, Douzgou et al 2019, Doummar et al 2021].
• Intellectual disability (ID) is present in a majority of individuals with CHD8-NDD.
  • The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
  • Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [Bernier et al 2014].
• Autism spectrum disorder (ASD) is diagnosed in most individuals with CHD8-NDD.
  • The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [Bernier et al 2014].
  • A majority of affected individuals (approximately 80%) with CHD8-NDD who have ASD also have ID, ranging in severity from mild-to-severe cognitive impairment.
• Other psychiatric conditions. Approximately 30% of individuals with CHD8-NDD have a psychiatric or behavioral diagnosis, with attention-deficit/hyperactivity disorder and anxiety disorders being the most commonly reported conditions.
  • However, the majority of reports in the current literature describe children and may underrepresent the prevalence of adult-onset psychiatric conditions.
  • There are several case reports of more severe adult-onset psychiatric manifestations, including psychosis, schizophrenia, and catatonia [McCarthy et al 2014, Kimura et al 2016, Ostrowski et al 2019].
  • Aggression and self-injury have also been noted in several individuals with CHD8-NDD [Stolerman et al 2016, Douzgou et al 2019, Alotaibi & Ramzan 2020, An et al 2020, Wu et al 2020, Kurtz-Nelson et al 2021].

Neurologic features

• Hypotonia. About 30% of affected individuals present with hypotonia [Bernier et al 2014, Merner et al 2016, Guo et al 2018, Douzgou et al 2019, Ostrowski et al 2019, Wu et al 2020, Doummar et al 2021].
• Seizures are reported in 10%-15% of published affected individuals. Typically, seizures are reported as brief or isolated events. Some individuals have abnormal EEG activity, such as nonspecific background slowing or subclinical seizure activity, without overt seizures observed [Bernier et al 2014, Wang et al 2018]. Types of seizures reported include febrile, absence, and tonic-clonic [Bernier et al 2014, Douzgou et al 2019, An et al 2020, Beighley et al 2020].
• Dystonia. Two individuals with CHD8-NDD and childhood-onset, generalized dystonia were reported by Zech et al [2020]. Another case series described two additional unrelated affected individuals with childhood-onset progressive dystonia [Doummar et al 2021]. In this study, neither individual's dystonia responded to pharmacologic therapy, but improvement was achieved with deep brain stimulation in both (see Management).
• Other neurologic features. Four individuals with CHD8-NDD were reported to have "cerebral palsy," although details about the phenotype, such as physiologic and topographic classification, were not provided [Bernier et al 2014, Moreno-De-Luca et al 2021].
• Neuroimaging. Results of brain imaging have been published for a small minority of affected individuals, and within this group about half had abnormal findings (12/22) [Wang et al 2018, Douzgou et al 2019, An et al 2020, Doummar et al 2021, Sadler et al 2021]. Published MRI findings, when details are available, include:
  • Ventriculomegaly (3 affected individuals)
  • Increased signal of periventricular white matter (2 affected individuals)
  • Cerebellar vermis atrophy (2 affected individuals)
  • Lack of white matter bulk (1 affected individual)
  • Chiari I malformation (3 affected individuals who all also had macrocephaly)

Macrocephaly and tall stature (typically defined as head circumference and height, respectively, that are more than 2 standard deviations above the mean for age and sex) are the most common findings among individuals with CHD8-NDD.

• Macrocephaly is sometimes apparent at birth but often develops or is accentuated in infancy [Wang et al 2018].
• Tall stature often becomes apparent in puberty [An et al 2020].
• While some individuals are also reported to be overweight [Douzgou et al 2019], more often they present with a slender habitus [Bernier et al 2014], possibly because of impaired adipogenesis [Kita et al 2018]. One case study described an individual with features reminiscent of Marfan syndrome [Yamada et al 2021].

Sleep disturbance. About 70% of individuals with CHD8-NDD have disrupted sleep, including difficulty with both initiation (delayed sleep onset) and maintenance (frequent night awakenings) of sleep. While sleep problems are common among many children with neurodevelopmental disorders, there is evidence that those with CHD8-NDD experience greater difficulty falling asleep [Earl et al 2021] and higher rates of frequent or prolonged awakenings at night, possibly as a result of developmental hyperserotonemia [Coll-Tané et al 2021].

Gastrointestinal issues. Various gastrointestinal problems are common in CHD8-NDD, with the most prevalent being recurrent constipation with or without periods of diarrhea [Bernier et al 2014, Wang et al 2018, An et al 2020]. Other gastrointestinal problems in isolated case reports include the following [Kimura et al 2016, Stolerman et al 2016, Douzgou et al 2019]:

• Inflammatory bowel disease
• Gastropathy (without further definition of the specific issues in this particular affected individual [Bernier et al 2014])
• Cyclical vomiting
• Gastroesophageal reflux
• Eosinophilic esophagitis

Facial features. Many individuals with CHD8-NDD share similar facial features, including a prominent supraorbital ridge, broad forehead with increased occipitofrontal circumference, widely spaced eyes, downslanted palpebral fissures, pointed chin, and large and/or posteriorly rotated ears [Talkowski et al 2012, Bernier et al 2014, Merner et al 2016, Alotaibi & Ramzan 2020, An et al 2020, Doummar et al 2021].

Other features reported (each in 1-2 affected individuals)

• Respiratory abnormalities. "Respiratory problems" were reported in two affected individuals, but no details were given [Bernier et al 2014].
• Feeding issues. Unspecified feeding problems were reported in two affected children [Guo et al 2018, Wu et al 2020].
• Endocrine
  • Autoimmune diabetes mellitus was reported in one individual with progressive dystonia [Doummar et al 2021].
  • Precocious puberty was diagnosed in two girls [Talkowski et al 2012, Bernier et al 2014].
• Malignancy. There have been two people older than age 40 years who developed tumors [Bernier et al 2014]. However, there is no evidence that individuals with CHD8-NDD have an increased risk over the general populuation risk of developing a malignancy, and no tumor surveillance guidelines for this condition have been published.

Prognosis. There is no evidence that life span in individuals with CHD8-NDD is shortened, although limited information is available on affected adults. One reported individual is alive at age 53 years [Doummar et al 2021], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

Large population-based studies are lacking, making prevalence estimates difficult to calculate for the general population.

In one study, nine in 2,446 individuals with autism spectrum disorder and eight in 3,730 individuals with a variety of neurodevelopmental disorders were found to have a de novo loss-of-function pathogenic CHD8 variant [Bernier et al 2014]. Another study estimated the prevalence of de novo CHD8 pathogenic variants to be as high as one in 500 in a population of individuals with autism spectrum disorder [Wilkinson et al 2015]. Pathogenic CHD8 variants are particularly prevalent (12 in 710, 1.7%) among individuals with both overgrowth and intellectual disability [Tatton-Brown et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CHD8-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for CHD8-NDD.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.

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

CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is an autosomal dominant disorder; the majority of affected individuals have a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands (85%-90%) reported to date with CHD8-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CHD8 pathogenic variant.
• An individual diagnosed with CHD8-NDD may have inherited a CHD8 pathogenic variant from a heterozygous parent. Details about heterozygous parents are scarce; one study reported three such parents with autistic features and nonverbal IQ scores in the borderline range [Guo et al 2018]. Another study described two parents who transmitted pathogenic CHD8 variants to their children, one from a father with autistic features, large head circumference, and recurrent sleep and gastrointestinal difficulties, and the other from a mother with mild autistic features, large head circumference, learning difficulties, and a history of childhood sleep problems [Bernier et al 2014]. There have been no published cases of parents who have the same pathogenic variant as their affected child but have no clinical features of the condition.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

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 known to have the CHD8 pathogenic variant identified in the proband, the sibs have a 50% chance of inheriting the variant.
• If the CHD8 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with CHD8-NDD has a 50% chance of inheriting the CHD8 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 CHD8 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 parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the CHD8 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

CHD8 encodes chromodomain-helicase-DNA-binding protein 8 (CHD-8), a DNA helicase involved in several processes including transcriptional regulation, epigenetic remodeling, promotion of cell proliferation, and regulation of RNA synthesis. CHD-8 acts as a repressor by remodeling chromatin structure and recruiting histone H1 to target genes, an example being suppressing p53/TP53-mediated apoptosis. CHD-8 acts as a negative regulator of Wnt signaling by regulating beta-catenin (CTNNB1) activity. CHD-8 also acts as a transcription activator by participating in U6 RNA polymerase III transcription through interactions with zinc finger protein 143.

CHD8 is primarily expressed in both the adult and fetal brain [Weissberg & Elliott 2021]. Interestingly, increased head circumference is the most replicated finding across both human and animal studies of CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD), with mouse and zebra fish models demonstrating an increase in brain volume that is the result of overproliferation of progenitor cells in the frontal cortex during development [Sugathan et al 2014, Durak et al 2016, Katayama et al 2016, Suetterlin et al 2018].

Preliminary research in a zebra fish model suggests that gastrointestinal problems associated with CHD8 pathogenic variants may be caused by a reduced number of vagal neural crest cells, decreased intestinal mobility, and increased inflammation (see bioRxiv).

Somatic CHD8 variants may play a role in the cell cycle of gastric/colorectal cancers [Kim et al 2011]; however, there is no current evidence that individuals with CHD8-NDD are at increased risk for developing cancer. Additional research, including longitudinal studies, is needed to determine whether individuals with germline CHD8 pathogenic variants are at increased risk for specific cancer types.

Heterozygous pathogenic loss-of-function variants cause CHD8-NDD. The majority of pathogenic variants reported in association with CHD8-NDD have been deletions and truncating and splicing variants. The gene is highly intolerant to loss-of-function variants in the general population [Karczewski et al 2020]. Some de novo missense variants that potentially disrupt function have been identified [O'Roak et al 2012, Bernier et al 2014, McCarthy et al 2014, Wang et al 2018].

Mechanism of disease causation. Heterozygous loss of function

Acknowledgments

This work was supported by the National Institute of Mental Health of the National Institutes of Health, grant numbers U01MH119705 and R01MH074090. The authors would also like to thank all of the individuals and families with CHD8-related neurodevelopmental disorder with overgrowth for their participation in these research studies.

Revision History

• 27 October 2022 (ma) Review posted live
• 22 March 2022 (cm) Original submission

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