What is the treatment for individuals with 16p11.2 deletions or duplications?

Treatment for 16p11.2 Deletions and Duplications

There is no specific cure or targeted pharmacological treatment for 16p11.2 copy number variants; management focuses on symptom-based interventions addressing the neurodevelopmental, neurological, and medical manifestations that arise from these genetic alterations. 1

Diagnostic Confirmation and Genetic Counseling

• Chromosomal microarray (CMA) is the first-tier diagnostic test for identifying 16p11.2 deletions and duplications, with this region representing one of the most common ASD-associated loci (occurring in 0.5-1% of individuals with autism spectrum disorders). 1
• Parental testing should be offered even when parents appear unaffected, as these CNVs show marked inter- and intrafamilial variability with reduced penetrance—meaning clinically normal parents may carry the same variant. 1
• Genetic counseling is essential to explain recurrence risks, which vary substantially: families with multiple affected siblings and female probands have higher risks (up to 32% for subsequent male children in families with two affected boys). 1

Neurodevelopmental and Psychiatric Management

Speech and Language Therapy

• Speech therapy is critical, as childhood apraxia of speech (CAS) occurs in 77% of children and 50% of adults with 16p11.2 deletion, with receptive and expressive language impairment present in 73% and 70% of children respectively. 2
• Intensive speech-language pathology should address both motor speech planning deficits (apraxia) and cognitive-linguistic errors (phonological disorders), as these commonly co-occur. 2

Behavioral and Educational Interventions

• Standard autism spectrum disorder interventions should be implemented when ASD is present, including applied behavior analysis and social skills training, as 16p11.2 CNVs are strongly associated with ASD. 1
• Individualized education plans (IEPs) must address motor delays affecting handwriting and physical education, coordinate with neurology for seizure management, and accommodate sleep disturbances that impair daytime attention. 3
• Social skills training is necessary to address increased vulnerability to bullying and social exploitation, particularly as social demands increase in adolescence. 3

Neurological Monitoring and Treatment

Seizure Management

• Screen for epilepsy, which occurs in 5-46% of individuals with 16p11.2 deletions, with epileptiform abnormalities found in up to 60% of cases. 1
• Standard antiepileptic medications should be used when seizures develop, with consideration of prophylactic treatment in high-risk cases given that seizures may further impair neurodevelopment. 1
• EEG monitoring is warranted when there is clinical suspicion of seizures or developmental regression. 1

Motor Dysfunction

• Physical and occupational therapy should target hypotonia (present in both deletions and duplications), abnormal agility, and delayed motor milestones. 4
• Monitor for action tremor particularly in duplication carriers, where it is highly prevalent. 4

Sleep Disorders

• Polysomnography should be performed to evaluate for obstructive sleep apnea and other sleep disturbances, which are common and significantly impact daytime functioning. 3
• Standard sleep hygiene interventions and medical management of identified sleep disorders should be implemented. 3

Medical Comorbidity Management

Weight and Metabolic Issues

• Nutritional counseling and weight management are essential, as 16p11.2 BP4-BP5 deletions are associated with hyperphagia, obesity, and macrocephaly, while duplications show a mirror phenotype with underweight and microcephaly. 5, 6
• The distal 16p11.2 BP2-BP3 deletion shows the most severe obesity phenotype (73.7% obesity rate, mean BMI SDS 3.2), requiring aggressive dietary and behavioral interventions. 5

Structural Abnormalities

• Neuroimaging should evaluate for Chiari I malformation/cerebellar tonsillar ectopia (common in deletions) and cerebral white matter/corpus callosum abnormalities with ventricular enlargement (common in duplications). 4
• Examine for sacral dimples, which are highly prevalent in both deletions and duplications and may indicate occult spinal dysraphism requiring further evaluation. 4

Reflexes and Tone

• Monitor for hyporeflexia and hypotonia in deletion carriers versus hyperreflexia in duplication carriers, as these reciprocal findings may guide prognosis and therapeutic approaches. 4

Emerging Therapeutic Approaches

• RHOA inhibition (specifically with Rhosin) has shown promise in preclinical iPSC-derived dopaminergic neuron models, rescuing the hyperactivation seen in 16p11.2 deletion neurons, though this remains investigational. 7

Critical Considerations

• Screen for additional genetic variants, as 18% of cases have variants of uncertain significance and 4% have a second definitive genetic diagnosis that may explain phenotypic severity or guide additional treatment. 5
• Coordinate multidisciplinary care with genetics, neurology, psychiatry, speech-language pathology, and developmental pediatrics to address the complex, variable phenotype. 1
• Transition planning should begin early, determining need for guardianship or supported decision-making and planning for post-secondary education or vocational training based on cognitive abilities. 3