SETD5-Related Neurodevelopmental Disorder

SETD5-related neurodevelopmental disorder (autosomal dominant intellectual disability type 23) is caused by haploinsufficiency of SETD5 (3p25.3), with intellectual disability, autism spectrum disorder, behavioural problems and mild dysmorphism. It is one of the commoner genetic causes of intellectual disability, and variants are usually de novo.

Pathophysiology. SETD5 is a methyltransferase that works with histone deacetylase complexes to regulate chromatin and transcription in neurons. Loss of one copy through a deletion or truncating variant impairs neuronal development.

Severity ranges from mild learning disability to severe intellectual disability.

Features overlap with other chromatin disorders, so genetic testing establishes the diagnosis.

• Intellectual disability, speech delay (often marked), and motor delay
• Autism spectrum disorder, ADHD, aggression, self-injury and sleep disturbance
• Hypotonia and feeding difficulty in infancy
• Dysmorphism: synophrys, a long and smooth philtrum, thin upper lip, and depressed nasal bridge
• Microcephaly or normal head size
• Seizures in a minority
• Congenital heart disease, and renal and genitourinary anomalies in some
• Hearing loss, strabismus and refractive error
• Gastrointestinal problems: reflux, constipation
• Short stature in a minority

• SETD5 sequencing with deletion and duplication analysis, or exome sequencing; chromosomal microarray for 3p25.3 deletions.
• Developmental and autism assessment.
• Echocardiography and renal ultrasound.
• Hearing and vision assessment.
• EEG and brain MRI if seizures or regression.
• Parental testing to confirm de novo origin.

• Development and education: early intervention, speech and language therapy with augmentative communication, occupational therapy and special education.
• Behaviour and ADHD: behavioural programmes, and 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.
• Anxiety and mood: sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily when needed.
• 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.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily.
• Cardiac, renal, hearing and vision care: treat anomalies and review yearly.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

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

Monitoring. Development and behaviour every 6 to 12 months. Vision and hearing yearly, and cardiac and renal review once at diagnosis, then as advised.

Referral and escalation. Refer to clinical genetics, developmental paediatrics and child psychiatry. Urgent for self-injury, seizures or regression.