Per our initial cohort, the clinical phenotype of GAND subjects was relatively consistent across our individuals. One exception was that GAND individuals with missense variants had a significant increase in risk of epilepsy compare to other variant subtypes. Current research is evaluating larger numbers of GAND children with less typical variant types (missense and splice-site) to determine if these differences are consistent with larger sample s.
Pregnancies were mostly without complications, with the exception of polyhydramnios (45%). Macrocephaly was frequently present at birth (69%) and became more common as children got older (91.8%). All subjects had global developmental delay and intellectual disability. All subjects had infantile hypotonia and delayed motor milestones, although most children learned to ambulate. A majority of subjects were noted to have infantile feeding difficulties and gastroesophageal reflux disease (82%).
These oro-mechanical issues were also associated with delayed and limited expressive language development in all subjects consistent with of childhood apraxia of speech. Receptive language was not as severely affected, with most children being able to follow multistep commands at older ages.
Epilepsy was present in a minority of subjects (24%) and could be of focal or primary generalized onset, with most children responding well to antiepileptic treatment.
Neuroimaging was abnormal in the majority of subjects (60%), with common features including enlarged extra-axial CSF spaces/ventriculomegaly, white matter signal abnormalities, hypomyelination, and thin corpora callosi.
Almost all subjects made good eye contact and exhibited social reciprocity.
Toilet training was not attained in the majority of subjects.
Most subjects had ophthalmological issues that included strabismus (88%), which was sometimes associated with astigmatism (41.3%), anisocoria (13.6%), and/or hypoplastic optic nerves (9%).
A minority of subjects were born with bicuspid aortic valves (~10%, compared with 2% in the general population), with two subjects requiring surgical intervention.
Facial features were evaluated in 37 GAND children of the initial cohort with the distinct “GAND facies” including a high wide forehead/frontal bossing (100%), prominent supraorbital ridges (62.2%), posteriorly angulated ears (59%), ocular hypertelorism (78.4%), downslanting palpebral fissures (45.6%), epicanthal folds (29.7%), prominent or bulbous nasal tip (83.8%), wide nasal base (35.1%), elongated wide nose (35.1%), short philtrum (51.3%), small recessed jaw (24.3%), and a pointed chin (91.9%). These features have been consistent since the original publication.
GATAD2B