Neurodevelopment
All reported individuals with biallelic loss-of-function variants in RABGAP1had severe global developmental delay and intellectual disability. Developmental impairment affects multiple domains and may be profound.
Two individuals had a diagnosis of attention-deficit/hyperactivity disorder, and one individual was undergoing assessment for possible autism spectrum disorder at the time of publication. The behavioral and neuropsychiatric spectrum remains incompletely characterized because of the small number of reported patients.
Head growth
Microcephaly is a prominent feature. Four of five reported individuals had significant microcephaly, with head circumference approximately 3–4 standard deviations below the mean. One individual did not have microcephaly and instead had a more unusual presentation with severe ventriculomegaly and hydrocephalus.
Neurological findings
Neurological abnormalities are variable. Reported findings include hypotonia, hypertonia, spasticity and hyperreflexia. Epilepsy has been reported, including absence seizures and focal-to-generalized tonic-clonic seizures. One individual experienced prolonged status epilepticus.
Hearing
Bilateral sensorineural hearing loss was present from birth in four of the five reported individuals. Hearing assessment should therefore be considered an important component of the clinical evaluation.
Ophthalmological findings
Congenital unilateral ptosis and exotropic strabismus have each been reported in one individual. Further patients are required to determine the frequency and significance of ophthalmological abnormalities.
Craniofacial features
Overlapping facial characteristics have been described. These include a beaked nose, microretrognathia and synophrys. These findings are not present in all individuals and should be regarded as supportive rather than diagnostic features.
Brain imaging
Brain MRI abnormalities are common. Four of five individuals had delayed myelination, reduced white matter volume and thinning of the corpus callosum. Ventriculomegaly was also reported.
One individual had severe ventriculomegaly associated with distal aqueductal stenosis and hydrocephalus, requiring multiple ventriculostomies. This individual also developed cortical atrophy following prolonged status epilepticus.
Other findings
Feeding difficulties and obesity were reported in the individual with severe hydrocephalus and epilepsy. The extent to which these findings are part of the core RABGAP1phenotype is currently uncertain.
Because only a small number of individuals have been reported, additional clinical features should be interpreted cautiously and the phenotype should continue to be expanded through systematic data collection.
These clinical details are directly reported in the primary study (see Publicationsbelow).
RABGAP1