3q29 Recurrent Deletion

Excerpt

Clinical characteristics: 3q29 recurrent deletion is characterized by neurodevelopmental and/or psychiatric manifestations including mild-to-moderate intellectual disability (ID), autism spectrum disorder (ASD), anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), executive function deficits, graphomotor weakness, and psychosis/schizophrenia. Age at onset for psychosis or prodrome can be younger than the typical age at onset in the general population. Neurodevelopmental and psychiatric conditions are responsible for the majority of the disability associated with the 3q29 deletion. Other common findings are failure to thrive and feeding problems in infancy that persist into childhood, gastrointestinal disorders (including constipation and gastroesophageal reflux disease [GERD]), ocular issues, dental anomalies, and congenital heart defects (especially patent ductus arteriosus). Structural anomalies of the posterior fossa may be seen on neuroimaging. To date more than 200 affected individuals have been identified.

Diagnosis/testing: The diagnosis of the 3q29 recurrent deletion is established by identification of a heterozygous 1.6-Mb deletion at the approximate position of chr3:195998129-197623129 in the reference genome (NCBI Build 38).

Management: Treatment of manifestations: Early speech and language therapy to address speech delays; physical/occupational therapy as needed to address motor issues; individualized education program for school-age children; care by a child psychiatrist/psychologist as needed for neuropsychiatric disorders with transfer of care to an adult psychiatrist when appropriate; cognitive behavioral therapy to address social disability and/or anxiety; adaptive behavior as needed; applied behavioral analysis for ASD; medication as needed for anxiety, ADHD, or psychosis; standard treatment of seizures; feeding therapy and consideration of gastrostomy tube as needed; routine management of musculoskeletal issues, GERD, strabismus, dental issues, congenital heart defects, recurrent ear infections, and epistaxis; consider behavioral treatment for enuresis; implement healthy sleep hygiene; family support.

Surveillance: At each visit: monitor developmental progress, educational needs, growth, nutrition, and feeding; assess for seizures, gastrointestinal issues, otitis, enuresis, and/or sleep issues. Annual assessment for neuropsychiatric manifestations and scoliosis; annual ophthalmology examination; dental examination every six months.

Evaluation of relatives at risk: If one of the proband's parents has the 3q29 recurrent deletion, it is appropriate to test at-risk sibs of the proband in order to identify those who would benefit from close assessment/monitoring of developmental milestones (in children) and monitoring for neuropsychiatric manifestations (in children and adults).

Genetic counseling: 3q29 recurrent deletion is an autosomal dominant disorder typically caused by a de novo deletion. If the proband represents a simplex case (i.e., a single affected family member) and neither parent has the 3q29 recurrent deletion or a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental mosaicism for the deletion. Each child of an individual with the 3q29 recurrent deletion has a 50% chance of inheriting the deletion. Once the 3q29 recurrent deletion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for the 3q29 recurrent deletion and preimplantation genetic testing are possible.