Submission Details

GNAO1 was first reported in relation to autosomal dominant (AD) rare genetic movement disorder in 2016 [Saitsu et al., PMID:25966631]. At least 10 unique variants have been reported in humans. These are all missense variants except for one variant that is predicted to result in loss of a splice donor. Evidence supporting this gene-disease relationship includes case-level data. All probands had hypotonia, developmental and motor delay, movement disorder, intellectual disability, and no to very limited speech. Some probands (6/20, 30%) had seizures, usually focal and well-controlled on anti-epileptic drugs. Many patients ( 8/20, 40%) had abnormal MRI or brain atrophy. There are many recurrent variants at two major residues: p.Arg209 and p.Glu246. This is because both of these sites are CpG sites that are prone to mutation. Variants identified include p.Arg209His, p.Arg209Gly, p.Arg209Cys, p.Arg209Leu, p.Glu246Lys and p.Glu246Gly. Seven probands improved with placement of deep brain stimulators into the bilateral internal globus pallidus (29758257). Variants in this gene have been reported in at least 20 probands in 7 publications. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease may be heterozygous gain-of-function (28747448), but more experimental evidence is needed. Of note, this gene has also been implicated in early-infantile epileptic encephalopathy. This has been assessed separately. In summary, GNAO1 is definitively associated with AD rare genetic movement disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Epilepsy Gene Curation Expert Panel on 2/19/2019 (SOP Version 6).