Epilepsy: GNAO1-Related Early Infantile Epileptic Encephalopathy and Neurodevelopmental Disorder with Involuntary Movement via the GNAO1 Gene

Early Infantile Epileptic Encephalopathy (EIEE) is a clinically and genetically heterogeneous neurodevelopmental disorder. The key feature of EIEE is onset of frequent and/or severe seizures within the first few weeks of life (Noh et al. 2012. PubMed ID: 22342633).

GNAO1-related early infantile epileptic encephalopathy is a rare genetic cause for early infantile epilepsy with median age of onset of 10 months (range 0–48 months). Major symptoms include intractable tonic seizures, absence of speech, severe motor and cognitive impairment with early postnatal lethality. Some patients present involuntary movements, hyperkinetic movements, facial dyskinesia, dysphagia, dystonia, chorea, athetosis and hyperalgesia. Initial EEG shows suppression-burst pattern, while MRI presents structural brain abnormalities including cerebral atrophy, corpus callosum dysgenesis and delayed myelination. Patients could be diagnosed as Ohtahara syndrome. Most patients are resistant to drug treatment, however, tetrabenazine and deep brain stimulation may be considered for treatments of dyskinesia (Nakamura et al. 2013. PubMed ID: 23993195; Danti et al. 2017. PubMed ID: 28357411; Marcé-Grau et al. 2016. PubMed ID: 27072799; Saitsu et al. 2016. PubMed ID: 25966631).

GNAO1-related early infantile epileptic encephalopathy and neurodevelopmental disorder with involuntary movement is inherited in an autosomal dominant manner. The disease is caused by pathogenic variants in the GNAO1 gene encoding guanine nucleotide-binding protein alpha activating activity polypeptide O (in the family of G protein, Gαo). In mammals, Gαo protein is a polypeptide in the group of alpha subunit (Gα). Gα subunit is bound to guanosine diphosphate (GDP) and forms the Gαβγ heterotrimeric complex. The Gαo protein is highly expressed in brain. Through G protein conducted signaling pathway, Gαo play important roles in maintaining normal brain function (Nakamura et al. 2013. PubMed ID: 23993195).

Pathogenic variants in GNAO1 only include missense and a deletion of 15 nucleotides. No large deletions/duplications in the GNAO1 locus have been reported (Human Gene Mutation Database). De novo pathogenic variants in GNAO1 gene are common (Nakamura et al. 2013. PubMed ID: 23993195; Marcé-Grau et al. 2016. PubMed ID: 27072799).

In a study of severe early infantile Epileptic Encephalopathy in patients diagnosed with Ohtahara Syndrome, 33% (4 out of 12) of cases were found to be caused by de novo pathogenic variants in GNAO1 (Nakamura et al. 2013. PubMed ID: 23993195).

To our knowledge, only a deletion of 15 nucleotides has been reported to date, which can be detected by sequencing (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the GNAO1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.