ASXL3-Related Disorder

Clinical characteristics: ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be issues with feeding. While dysmorphic facial features have been described, they are typically nonspecific. Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers. Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies.

Diagnosis/testing: The diagnosis of ASXL3-related disorder is established in a proband by identification of a heterozygous pathogenic variant in ASXL3 by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy; gastrostomy tube placement for those with persistent feeding issues; anti-reflux medication and/or fundoplication for those with gastroesophageal disease; standard treatment for epilepsy, joint contractures, sleep apnea, dental anomalies, strabismus and/or refractive error, and developmental delay / intellectual disability.

Surveillance: At each visit: Measurement of growth parameters and nutritional status; assessment of developmental progress, behavioral issues, new neurologic manifestations (change in tone, seizure onset and/or frequency), mobility and self-help skills, as well as signs and symptoms of sleep disturbance. Dental evaluation every six months after age three years or as clinically indicated. At least annual ophthalmology evaluation.

Genetic counseling: ASXL3-related disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with ASXL3-related disorder have the disorder as the result of a pathogenic variant inherited from a parent. If the ASXL3 pathogenic variant identified in the proband is not identified in either parent, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental germline mosaicism. Once the ASXL3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.