ADNP Syndrome

ADNP syndrome is a neurodevelopmental disorder caused by de novo heterozygous variants in ADNP (20q13.13), one of the commonest single gene causes of syndromic autism. It is also known as Helsmoortel-Van der Aa syndrome. This article concentrates on the genetics and diagnostic approach.

Pathophysiology

ADNP (activity dependent neuroprotector homeobox) is a chromatin binding protein that interacts with the BAF complex and heterochromatin protein 1, and controls neuronal differentiation. Most pathogenic variants are truncating changes in the last exon, which escape nonsense mediated decay and are thought to act through a dominant negative effect.

Variants outside the last exon, and the position of the change, relate to severity.

Each variant class produces a distinct DNA methylation signature in blood, which helps interpret uncertain variants.

• Intellectual disability of variable degree, with speech delay
• Autism spectrum disorder and attention problems
• Hypotonia, feeding difficulty and gastrointestinal problems (constipation, reflux)
• Visual problems: hypermetropia, strabismus, cortical visual impairment
• Early eruption of primary teeth, and later dental problems
• Sleep disturbance and behavioural difficulties
• Epilepsy in a minority, and structural brain anomalies in some
• Congenital heart defects, hearing loss, and endocrine problems
• Mild facial dysmorphism: prominent forehead, wide and high nasal bridge, and thin upper lip

• ADNP sequencing, within an autism and intellectual disability gene panel or exome sequencing. Single nucleotide variants in the last exon are the commonest finding.
• Peripheral blood DNA methylation (episignature) analysis to classify variants of uncertain significance.
• Parental testing to confirm de novo origin.
• Developmental and autism assessment.
• Ophthalmology and audiology assessment.
• Echocardiography and thyroid function.

• Developmental and educational care: early intervention, speech and communication therapy, applied behavioural support and special education.
• Vision: spectacles for hypermetropia, strabismus treatment, and assessment for cortical visual impairment.
• Dental care: early dental review because of early tooth eruption and crowding.
• Sleep: sleep hygiene and melatonin 2 to 5 mg orally 30 to 60 minutes before bed (up to 10 mg if needed).
• Gastrointestinal care: macrogol 0.4 to 0.8 g/kg daily (adults 1 to 3 sachets) for constipation, and omeprazole 0.7 to 1 mg/kg daily for reflux.
• Behaviour and mental health: ADHD treated with methylphenidate 5 mg orally once or twice daily increasing weekly by 5 to 10 mg to a usual maximum of 60 mg daily after cardiac review, and anxiety with sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily.
• Cardiac and endocrine care: echocardiography once and treatment of defects, and thyroid function yearly.
• Genetic counselling: de novo variants carry a low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue mental health and behavioural support and plan transition.

Monitoring. Development and behaviour every 6 to 12 months. Vision, hearing and thyroid function yearly, and dental review every 6 months.

Referral and escalation. Refer to clinical genetics, developmental paediatrics and ophthalmology. Urgent for seizures, regression or severe behavioural crisis.