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 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. 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