GNAO1

The GNAO1 gene encodes a key signaling protein in the brain and plays a central role in regulating neuronal activity through G protein-coupled receptor pathways. 

Mutations in GNAO1 are increasingly recognized as a cause of early-onset movement disorders, epilepsy, and neurodevelopmental delay, making accurate diagnosis and genetic testing essential for affected individuals.

What is GNAO1?

GNAO1 is a gene that codes a key component of G proteins. 

Gene and Protein

GNAO1 encodes the alpha subunit of the Go heterotrimeric G protein, one of the most abundant signaling proteins in the brain. It is mainly found in areas involved in movement, memory, and emotion, such as the striatum, cerebellum, and hippocampus.

G Proteins and Signal Transduction

G proteins act like switches inside cells. When activated by G protein-coupled receptors (GPCRs) on the cell surface, they trigger changes inside the cell that influence everything from heart rate to brain activity. 

The Gα-subunit helps regulate neurotransmitter signaling, modulates ion channels, and controls brain development.

When is GNAO1 Genetic Testing Relevant?

Genetic testing for GNAO1 is recommended in individuals who present with unexplained movement disorders, such as:

• Dystonia (involuntary muscle contractions)
• Chorea (jerky movements)
• Athetosis (slow, writhing motions)
• Developmental and Epileptic Encephalopathies (DEEs), especially if seizures begin in infancy
• Global developmental delay or intellectual disability, with or without seizures or abnormal movements

Differential Diagnosis

GNAO1 testing helps distinguish these symptoms from other genetic conditions with similar features, such as ADCY5-related dyskinesia or SCN1A-related epilepsies

Genetic Counseling

Genetic counseling is essential before and after testing. It helps families understand the cause, inheritance pattern, recurrence risk, and options for future pregnancies.

GNAO1 Genetic Testing: Test Procedure and Interpretation

Testing for GNAO1 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for GNAO1 genetic testing are considered to be without mutations that can alter the activity of the GNAO1 proteins.

What Do Specific GNAO1 Mutations Mean?

GNAO1 mutations may have the following clinical significance:

Genetic Confirmation

Finding a pathogenic (disease-causing) variant in GNAO1 confirms a diagnosis of a GNAO1-related disorder. These conditions are typically autosomal dominant, but most mutations occur de novo (new in the child, not inherited).

Genotype–Phenotype Correlations

Some mutations have been linked to specific symptoms:

• p.Gly203Arg and p.Gly40Trp: linked to severe epilepsy
• p.Arg209His/Cys: linked to severe movement disorders
• I344del: often associated with a milder, non-progressive course

However, there is significant variability. Two individuals with the same mutation may have very different symptoms.

What Does the Absence of a Pathogenic Mutation Mean?

A negative test result doesn’t rule out a genetic cause for the symptoms. Other genes may be involved. If clinical suspicion remains high, further testing such as whole-exome sequencing (WES) or a comprehensive gene panel may be needed.

GNAO1-Related Disorders: Clinical Overview

The following section provides a brief clinical overview of GNAO1-related disorders:

Associated Conditions

• Developmental and Epileptic Encephalopathy 17 (DEE17): Early-onset seizures, severe developmental delay, hypotonia, hyperkinetic movements
• Neurodevelopmental Disorder with Involuntary Movements (NEDIM): Chorea, dystonia, developmental delay, seizures less common

Symptoms

• Epilepsy: Seizures usually begin in infancy, may be drug-resistant
• Movement Disorders: Chorea, dystonia, athetosis, tremor, often severe
• Neurodevelopmental Delay: Hypotonia, intellectual disability, feeding problems

Some patients have life-threatening movement episodes called hyperkinetic crises, often triggered by stress or illness.

Diagnosis and Testing

Molecular testing (gene panels or WES) detects most pathogenic variants.

Deletions or duplications may require additional tests (e.g., microarray).

Whole-exome sequencing is especially useful in undiagnosed children with movement disorders and normal MRI results.

Treatment and Management

There is no cure for GNAO1-related disorders. Management is supportive and individualized:

Seizure Control

• Antiseizure medications (ASMs), often GABAergic agents
• Hormonal therapy (e.g., vigabatrin) for infantile spasms
• Some cases are drug-resistant

Movement Disorder Treatment

• Medications: Tetrabenazine, clonazepam, trihexyphenidyl, baclofen
• Deep brain stimulation (DBS): Effective in some patients with refractory dystonia or crisis episodes

Supportive Therapies

The following supportive therapies may be considered:

• Physical, occupational, and speech therapy
• Nutritional support (feeding tubes as needed)
• Augmentative communication tools

Prognosis and Genetic Counseling

Prognosis is highly variable. Some patients have stable function, while others experience progressive decline. Early deaths may occur due to seizures or movement crises.

Genetic Counseling: most cases are de novo, but germline mosaicism may lead to recurrence in ~5–15% of families.

Families with an identified mutation can pursue prenatal or preimplantation genetic testing.

Key Takeaways for Clinicians

Consider GNAO1 testing in children with early-onset epilepsy, unexplained hyperkinetic movements, or severe developmental delay.

Diagnosis often guides treatment decisions, including use of DBS.

Multidisciplinary care is essential for optimizing quality of life and managing complications.

Stay updated on emerging gene-targeted therapies as research advances.