CHD4 Neurodevelopmental Disorder

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.