Abstracts

Rationale: We describe six previously unreported cases of GNAO1 related neurodevelopmental disorders and investigate genetic and phenotypic patterns across the field of reported cases. Methods: Our research was conducted with approval from the Institutional Review Board at Boston Children’s Hospital. GNAO1 variants were identified in six individuals through clinical testing, four via whole exome sequencing and two via next-generation sequencing gene panel testing. Other cases discussed were identified through a review of the literature. Results: Six new patients with GNAO1 variants were identified (2 male and 4 female, aged 2-20 years). All six have epilepsy; five with early onset epileptic encephalopathy and one with early onset focal epilepsy. Five have movement abnormalities and developmental delay. Two have microcephaly, three are hypotonic, and two are hypertonic. Including these six individuals, there are 40 cases of GNAO1-related neurodevelopmental disorders in the literature. Of those, 33 individuals (82.5%) have movement abnormalities, 26 (65%) have epilepsy, and 19 (47.5%) have both movement abnormalities and epilepsy. Movement abnormalities include chorea, dystonia, dyskinesia, choreoathetosis, ballismus, spasticity, stereotypies, athetosis, and ataxia. Epilepsy phenotypes included epileptic encephalopathy, focal epilepsy, and epilepsy with generalized and focal seizures. All individuals with complete phenotyping had developmental delay. Microcephaly and tone issues were also common (25% and 75%, respectively). On MRI, atrophy (42.5%), corpus callosum findings (27.5%), and delayed myelination (12.5%) were the most common abnormalities noted, though 35% had a reportedly normal MRI. Those with a normal MRI were less likely to have epilepsy (28.6%).Patient 4 has a VUS, D273V, in transcript NM_138736.2. Previously, no pathogenic variants have been reported in this transcript. Based on patient 4’s phenotype and similar locations of variants in transcript NM_020988.2, we believe that this variant is likely to be pathogenic. Parental testing has not been completed but would help clarify the significance of this finding.Of the identified variants in our 6 cases and the literature, 39 out of 40 were in the GTP binding domains of the protein. Four patients in our cohort carried a variant in residue 40, previously reported in one individual. Additionally, variants in residues 203, 209 and 246 are reported numerous times in the literature.Previously, two other confirmed sibling pairs have been reported as well as one individual whose older sibling with a similar clinical presentation had passed away before testing was possible. Our cohort adds another sibling pair to the literature. Conclusions: The epilepsy and movement disorder phenotypes described here have been prevalent among reported cases. Other features such as microcephaly, hypotonia, and developmental delay, have emerged as common features for these individuals as well. Here we note potential hotspots within the gene as well as a potential first variant in the C-terminal portion of transcript NM_138739.2. Funding: Child Neurology FoundationDravet Syndrome FoundationNeurology Foundation Boston Children's Hospital