Submission Details

GNAO1 was first reported in relation to autosomal dominant (AD) early infantile epileptic encephalopathy in 2013 [Nakamura et al. PMID: 23993195]. At least 13 unique variants have been reported in humans. These are all missense variants except for one variant that results in a deletion. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 16 probands in 11 publications. The maximum score for genetic evidence (12 pts) has been reached. Experiments performed on non-patient (HEK-293T) cells transfected with human GNAO1 cDNA demonstrated that several variants had reduced expression and loss-of-function in a cAMP inhibition assay. Notably, variant p.Gly203Arg demonstrated gain-of-function effects, but these probands have more prominent movement disorders compared to probands with other variants. The mechanism for disease may be heterozygous loss-of-function [Feng et al. PMID: 28747448], however more experimental evidence is needed to delineate contributions of loss versus gain of function mechanisms. Of note, this gene has also been implicated in autosomal dominant rare genetic movement disorder. This has been assessed separately. In summary, GNAO1 is definitively associated with autosomal dominant early infantile epileptic encephalopathy. 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 GCEP on 12/18/2018.