Pathogenic variants in the TRAPPC6Bgene cause a multisystem neurodevelopmental disorder (Figure 1).
All individuals with a mutation in the TRAPPC6Bgene have these features:
• Microcephaly
◦ Typically present at birth (primary microcephaly) or develops postnatally
◦ Non-progressive in the majority of patients
• Global Developmental Delay and Intellectual Disability
◦ Ranges from moderate to severe
◦ Expressive language severely impaired; many patients are non-verbal
◦ Motor milestones are delayed; some patients achieve independent walking at a later age
• Epilepsy
◦ Early-onset, usually in infancy or early childhood
◦ Seizure types include generalized tonic-clonic, absence, and focal seizures
Most individuals with a mutation in the TRAPPC6Bgene also have:
• Autistic features
◦ Poor social interaction, impaired eye contact, repetitive/stereotypic behaviors
• Hypotonia
◦ Generalized, may contribute to delayed motor milestones
• Brain structural abnormalities on MRI
◦ Cortical atrophy
◦ Thin or hypoplastic corpus callosum
◦ Cerebellar and brainstem atrophy
◦ White matter signal abnormalities / enlarged lateral ventricles
Other less frequently reported clinical features:
• Movement disorders: spasticity, dystonia
• Behavioral problems: aggression, self-injurious behavior, hyperactivity, anxiety
• Variable dysmorphic features: bitemporal narrowing, deep-set eyes, prominent ears, broad nasal root
• Extrapyramidal symptoms in older patients (hand tremors, unstable gait)
Penetrance
Penetrance appears to be complete for core features (microcephaly, DD/ID, epilepsy). The severity of intellectual disability and occurrence of additional features are variable among individuals, even within the same family.
Prognosis
The prognosis is generally poor for severely affected individuals. Most patients require lifelong support. A subset of older patients may show signs of neurological deterioration, including worsening of ataxic gait and loss of psychomotor skills.
Figure 1: Clinical characteristics of individuals with a pathogenic variant in the TRAPPC6Bgene
