GNAO1 – Neurodevelopmental Disorder with Involuntary Movements

Neurodevelopmental disorder with involuntary movements is an autosomal dominant pediatric condition characterized by psychomotor delay, hypotonia, and hyperkinetic involuntary movements. Heterozygous de novo and mosaic missense variants in GNAO1 underlie this phenotype, with gain-of-function effects on the Gα_o protein signaling cascade ([PMID:31907305]).

Genetic evidence includes five unrelated patients from two families exhibiting parental gonadal mosaicism ([PMID:35782616]), two additional affected siblings in a familial deep brain stimulation cohort ([PMID:26060304]), and two sporadic cases from a phenotypic spectrum series presenting involuntary movements and severe developmental delay ([PMID:25966631]). In total, nine unrelated probands have been described, with segregation of the pathogenic allele in four additional affected relatives. These findings support a Strong clinical validity classification per ClinGen criteria.

Variants are predominantly missense, clustering at codons Gly203, Arg209, Glu246, and splice‐region changes such as c.724-8G>A. The recurrent c.626G>A (p.Arg209His) hotspot has been observed in multiple unrelated probands and is functionally characterized in vivo. No deep‐intronic or structural variants have been reported to date.

Functional studies demonstrate that the p.Arg209His mutant accelerates nucleotide exchange by ~6.2-fold without altering protein expression, driving hyperlocomotion in a heterozygous knock-in mouse model that is ameliorated by risperidone ([PMID:31907305]). Additional invertebrate and mammalian assays confirm gain-of-function or dominant-negative mechanisms, with restoration of wild-type behavior via gene replacement in mice.

Mechanistically, pathogenic variants disrupt GTPase cycling of Gα_o, leading to aberrant downstream signaling and network hyperexcitability. Preclinical AAV9-mediated GNAO1 gene therapy reverses hyperlocomotion in mutant mice without increasing seizure susceptibility, paving the way for targeted interventions ([PMID:38866563]).

No conflicting reports have been published to dispute this association. Together, the accumulation of case data, segregation in multiple families, and concordant functional models fulfill ClinGen’s thresholds for a Strong gene–disease relationship.

Key Take-home: GNAO1 genetic testing is recommended for early-onset movement disorders with hypotonia and hyperkinetic features, as prompt diagnosis can inform therapeutic strategies including pharmacologic and gene therapy approaches.

References

• Molecular genetics and metabolism reports • 2022 • Gonadal mosaicism in GNAO1 causing neurodevelopmental disorder with involuntary movements; two additional variants. PMID:35782616
• Journal of child neurology • 2016 • Progressive Movement Disorder in Brothers Carrying a GNAO1 Mutation Responsive to Deep Brain Stimulation. PMID:26060304
• European journal of human genetics : EJHG • 2016 • Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. PMID:25966631
• The Journal of pharmacology and experimental therapeutics • 2020 • Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone. PMID:31907305
• The Journal of pharmacology and experimental therapeutics • 2024 • AAV9-Mediated Intrastriatal Delivery of GNAO1 Reduces Hyperlocomotion in Gnao1 Heterozygous R209H Mutant Mice. PMID:38866563

Evidence Based Scoring (AI generated)