Clinical characteristics.

CHD4 neurodevelopmental disorder (CHD4-NDD) is associated with developmental delay, speech delay, and usually mild-to-moderate intellectual disability. Variability between individuals with CHD4-NDD is significant, and a few have normal intelligence. Other manifestations can include brain anomalies, heart defects, and skeletal abnormalities; less common features are hypogonadism in males, hearing impairment, and ophthalmic abnormalities. Most affected individuals have mild nonspecific dysmorphic facial features with or without macrocephaly.

Diagnosis/testing.

The diagnosis of CHD4-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in CHD4 identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental delay / intellectual disability, cervical spine instability and risk of spinal cord compression, refractive errors and strabismus, hearing impairment, congenital heart defects, behavioral issues, growth delay, hypogonadism in males, and renal anomalies are managed per standard care.

Surveillance: Follow up of the common manifestations at each clinic visit.

Agents/circumstances to avoid: Activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks) because of the possible increased risk for cervical spine instability and spinal cord compression.

Genetic counseling.

CHD4-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. If the CHD4 pathogenic variant identified in the proband is not identified in either parent, the risk to sibs is low (~1%) but greater than that of the general population because of the possibility of parental germline mosaicism. Once the CHD4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

CHD4-NDD should be considered in individuals with the following clinical and brain MRI findings.

Clinical findings. Developmental delay or mild-to-moderate intellectual disability AND any of the following features presenting in infancy or childhood:

• Generalized hypotonia of infancy
• Macrocephaly or relative macrocephaly
• Congenital heart defects (septal defects, conotruncal anomalies, and valvular abnormalities)
• Skeletal and limb anomalies (vertebral fusion, carpal/tarsal coalition, syndactyly, polydactyly)
• Hypogonadism in males (cryptorchidism and/or microphallus)
• Ophthalmologic abnormalities (strabismus, hypermetropia, astigmatism)
• Hearing impairment (conductive and/or sensorineural)
• Moyamoya disease with congenital or infantile stroke

Brain MRI findings. Brain anomalies including the following (detected in 92% [22/24] of affected individuals):

• Mild-to-moderate ventriculomegaly (in 41%)
• Chiari 1 malformation (29%)
• Hydrocephalus requiring shunting (18%)
• Other. Thin corpus callosum and syringomyelia

Establishing the Diagnosis

The diagnosis of CHD4-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in CHD4 identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous CHD4 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing in any child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA), which uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis.

If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of CHD4, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability (ID) multigene panel that includes CHD4 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. Of note, given the rarity of CHD4-NDD, some panels for intellectual disability may not include this gene. (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.
• Comprehensive genomic testing does not require the clinician to determine which gene is 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 ID, whereas some multigene panels may not. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by exome sequencing. Note: To date such variants have not been identified as a cause of CHD4-NDD.
  Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

CHD4 neurodevelopmental disorder (CHD4-NDD) is associated with developmental delay, speech delay, and usually mild-to-moderate intellectual disability. Variability among individuals with CHD4-NDD is significant, and some have normal intelligence. Other manifestations can include brain anomalies, heart defects, and skeletal abnormalities; less common features are hypogonadism in males, hearing impairment, and ophthalmic abnormalities. Most affected individuals have mild nonspecific dysmorphic facial features with or without macrocephaly.

To date, 33 individuals have been identified with a heterozygous CHD4 pathogenic missense variant or in-frame insertion/deletion [Sifrim et al 2016, Weiss et al 2016, Weiss et al 2020, and unpublished data]. The following description of CHD4-NDD phenotypic features is based on these reports.

Developmental delay (DD) and intellectual disability (ID). The majority of individuals have developmental delay. Speech delay is common, but the majority communicate verbally using short sentences; absence of speech has not been reported. A cognitive assessment identified intellectual disability in the mild-to-moderate range in 82%; in four individuals IQ score was in the low normal or borderline range.

The average age of independent ambulation is 30 months. Three children achieved independent ambulation after age five years.

Other neurodevelopmental features include hypotonia during infancy and early childhood. While some infants have feeding difficulties, few require nasogastric tube feeding or gastrostomy.

Hydrocephalus requiring shunting has been associated with intellectual disability ranging from mild to moderate.

Behavioral or psychiatric problems are not a frequent finding. Autism spectrum disorder was reported in three individuals and attention-deficit disorder, impulsivity, and anxiety were reported in three.

Growth. The majority are born after an uneventful pregnancy with an average birth weight and head circumference. Some individuals develop macrocephaly; a few have microcephaly. Short stature is seen in 30%. Seven of 30 individuals had obesity at late childhood or adulthood. Growth hormone deficiency was reported in four individuals, all of whom were treated with growth hormone with an overall good response.

Congenital heart defects include septal defects, conotruncal anomalies, and valve anomalies. To date the following malformations (by frequency) have been reported: atrial septal defect, ventricular septal defect, pulmonary stenosis, patent ductus arteriosus, tetralogy of Fallot, mitral valve anomalies, Ebstein anomaly, and truncus arteriosus.

Skeletal and limb anomalies. The most common are hand or foot syndactyly, polydactyly, scoliosis (acquired), vertebral anomalies (mainly cervical fusions), and tarsal or carpal coalition. In those with cervical vertebral anomalies, the risk for cervical instability is increased.

Because some individuals with CHD4-NDD did not have a skeletal survey, the true frequency of bone fusions and other skeletal anomalies could be higher.

Hypogonadism is common in males. When performed, the hormonal profile was consistent with hypogonadotropic hypogonadism.

To date, there are no reports of hypogonadism or infertility in females; however, the majority of individuals reported to date are children.

Sensory impairment. Of those with hearing impairment, the majority of affected individuals have sensorineural hearing loss; a few have conductive or mixed hearing impairment. Recurrent otitis media is not common.

Significant vision impairment has not been reported, but ophthalmic anomalies (by frequency) include: strabismus, astigmatism, hypermetropia, glaucoma, small optic nerves, iris coloboma, and myopia.

Moyamoya disease. Of the three children who had a stroke after birth or during infancy, two were diagnosed with moyamoya disease. A link between CHD4 variants and moyamoya disease has also been described by Pinard et al [2020].

Facial features. Mild nonspecific dysmorphic features observed in some individuals include widely spaced eyes, periorbital fullness, a short nose, and a square face.

Cancer risk. Cancer has not been reported in individuals with CHD4-NDD.

Prognosis. It is unknown whether life span in CHD4-NDD is abnormal. One individual is alive at age 30 years [Weiss et al 2020], demonstrating that survival into adulthood is possible. However, severe congenital abnormalities may shorten the life span. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with CHD4-NDD are underrecognized and underreported.

Genotype-Phenotype Correlations

The majority of CHD4 variants are missense substitutions that fall in the ATPase / C terminal helicase domain (amino acids 724-1281). Data to date are insufficient to support genotype-phenotype correlations.

Penetrance

Because the vast majority of individuals with CHD4-NDD reported to date have de novo variants, it is currently thought the penetrance is close to 100%.

Prevalence

CHD4-NDD is rare. The authors are aware of approximately 50 affected individuals worldwide.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CHD4 neurodevelopmental disorder (CHD4-NDD), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Avoid activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks) because of the possible increased risk for cervical spine instability.

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

CHD4 neurodevelopmental disorder (CHD4-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Almost all probands reported to date with CHD4-NDD have the disorder as a result of a de novo CHD4 pathogenic variant.
• Presumed parent-to-child transmission was reported in one family in which the parent had features of CHD4-NDD; however, the presumed transmitting parent was not available for molecular genetic testing [Weiss et al 2020].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the CHD4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of germline mosaicism have been reported to date.
• Theoretically, if the parent is the individual in whom the CHD4 pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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 has the CHD4 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the CHD4 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 CHD4-NDD has a 50% chance of inheriting the CHD4 pathogenic variant.

Other family members. Given that almost all probands with CHD4-NDD reported to date have the disorder as a result of a de novo CHD4 pathogenic variant, the risk to other family members is presumed to be low.

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

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo CHD4 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.

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

CHD4 encodes an ATP-dependent chromatin remodeler, a core component of the nucleosome remodeling and histone deacetylation (NuRD) complex that is widely expressed and acts mainly, but not exclusively, as a transcriptional repressor. It contains a histone deacetylase (HDAC1/2) and methyl-CpG binding domain protein (MBD2) which bind histone H3 and methylated DNA, respectively. The NuRD complex is involved in multiple processes including stem cell differentiation, embryonic development, cell cycle progression, and DNA damage repair.

Mechanism of disease causation. A dominant-negative mechanism is suspected but not proven. Most reported CHD4 variants are missense variants or in-frame insertions/deletions. In addition, a few individuals with de novo loss-of-function CHD4 variants have been reported; however, the clinical significance of these variants is unclear due to lack of functional studies or a strong phenotypic similarity.

Literature Cited

• Pinard A, Guey S, Guo D, Cecchi AC, Kharas N, Wallace S, Regalado ES, Hostetler EM, Sharrief AZ, Bergametti F, Kossorotoff M, Hervé D, Kraemer M, Bamshad MJ, Nickerson DA, Smith ER, Tournier-Lasserve E, Milewicz DM. The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. Genet Med. 2020;22:427–31. [PMC free article: PMC7673309] [PubMed: 31474762]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Turki SH, Thienpont B, McRae J, Fitzgerald TW, Singh T, Swaminathan GJ, Prigmore E, Rajan D, Abdul-Khaliq H, Banka S, Bauer UM, Bentham J, Berger F, Bhattacharya S, Bulock FA, Canham N, Colgiu IG, Cosgrove C, Cox H, Daehnert I, Daly A, Danesh J, Fryer A, Gewillig M, Hobson E, Hoff K, Homfray T, Kahlert AK, Ketley A, Kramer HH, Lachlan K, Lampe AK, Louw JJ, Manickara AK, Manase D, McCarthy KP, Metcalfe K, Moore C, Newbury-Ecob R, Omer SO, Ouwehand WH, Park SM, Parker MJ, Pickardt T, Pollard MO, Robert L, Roberts DJ, Sambrook J, Setchfield K, Stiller B, Thornborough C, Toka O, Watkins H, Williams D, Wright M, Mital S, Daubeney PE, Keavney B, Goodship J, Abu-Sulaiman RM, Klaassen S, Wright CF, Firth HV, Barrett JC, Devriendt K, FitzPatrick DR, Brook JD, Hurles ME, et al. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet. 2016;48:1060–5. [PMC free article: PMC5988037] [PubMed: 27479907]
• Weiss K, Lazar HP, Kurolap A, Martinez AF, Paperna T, Cohen L, Smeland MF, Whalen S, Heide S, Keren B, Terhal P, Irving M, Takaku M, Roberts JD, Petrovich RM, Schrier Vergano SA, Kenney A, Hove H, DeChene E, Quinonez SC, Colin E, Ziegler A, Rumple M, Jain M, Monteil D, Roeder ER, Nugent K, van Haeringen A, Gambello M, Santani A, Medne L, Krock B, Skraban CM, Zackai EH, Dubbs HA, Smol T, Ghoumid J, Parker MJ, Wright M, Turnpenny P, Clayton-Smith J, Metcalfe K, Kurumizaka H, Gelb BD, Baris Feldman H, Campeau PM, Muenke M, Wade PA, Lachlan K. The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis. Genet Med. 2020;22:389–97. [PMC free article: PMC8900827] [PubMed: 31388190]
• Weiss K, Terhal PA, Cohen L, Bruccoleri M, Irving M, Martinez AF, Rosenfeld JA, Machol K, Yang Y, Liu P, Walkiewicz M, Beuten J, Gomez-Ospina N, Haude K, Fong CT, Enns GM, Bernstein JA, Fan J, Gotway G, Ghorbani M, van Gassen K, Monroe GR, van Haaften G, Basel-Vanagaite L, Yang XJ, Campeau PM, Muenke M, et al. De novo mutations in CHD4, an ATP-dependent chromatin remodeler gene, cause an intellectual disability syndrome with distinctive dysmorphisms. Am J Hum Genet. 2016;99:934–41. [PMC free article: PMC5065651] [PubMed: 27616479]

Revision History

• 3 September 2020 (bp) Review posted live
• 28 January 2020 (kw) Original submission