Clinical Guidance

More than 200 individuals with pathogenic variants in GNAO1 have been reported in the literature to date. To date, genotype-phenotype correlations have been described for several recurrent GNAO1 variants: one splicing variant and variants at five hot spot residues (p.Gly40, p.Gly203, p.Arg209, p.Glu237, and p.Glu246). These recurrent variants account for approximately half of affected individuals reported to date . In addition, accumulating data may point to haploinsufficiency variants being associated with milder phenotypes, without epileptic encephalopathy or severe global developmental delay or intellectual disability [, , , , ]. Table 2. GNAO1-Related Disorder: Genotype-Phenotype Correlations

Source: GeneReviews — "GNAO1-Related Disorder"

Genetic testing for GNAO1 is available. Testing is considered confirmatory for diagnosis.

Biomarker and diagnostic research for neurodevelopmental disorder with involuntary movements has been reported in the published literature.

GNAO1-Related Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

| Eval by pediatric or adult neurologist | • For evidence of DD/ID, epilepsy, movement disorder

• For those w/abnormal movements, eval by movement specialist is recommended.

• Perform EEG if seizures are a concern. Distinguishing between dystonia seizure can be a challenge.

• Consider brain MRI if not previously performed.

Dysarthria

| Communication assessment/ speech-language therapy assessment | • For all persons w/speech delay, ensure hearing is normal.

• Evaluate need for communication aids.

Development

| Developmental assessment cognitive function eval | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ individual education program

Neurobehavioral/Psychiatric

| Neuropsychiatric eval | Screening for behavior concerns incl sleep disturbances, ADHD, anxiety, /or findings suggestive of ASD

Musculoskeletal/ADL

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

Source: GeneReviews — "GNAO1-Related Disorder"

• Eval of nutritional status safety of oral intake

| At each visit

Gastrointestinal

| Monitor for constipation.

Respiratory

| Monitor for evidence of aspiration, respiratory insufficiency.

Neurologic

| • Monitor those w/seizures as clinically indicated.

• Assess for new manifestations such as seizures, changes in tone, movement disorders.

Development

| Monitor developmental progress educational needs.

Neurobehavioral/Psychiatric

| Behavioral assessment for anxiety, attention, aggressive or self-injurious behavior

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, self-help skills; clinical eval of hip spine for those who are non-ambulatory /or severely hypotonic

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "GNAO1-Related Disorder"

Phenotype severity distribution: 1 always present feature, 9 common features.