Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region

Abstract

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.1528-1167Kelly, McKenna <br />Park, Meredith <br />Mihalek, Ivana <br />Rochtus, Anne <br />Gramm, Marie <br />Pérez-Palma, Eduardo <br />Axeen, Erika Takle <br />Hung, Christina Y <br />Olson, Heather <br />Swanson, Lindsay <br />Anselm, Irina <br />Briere, Lauren C <br />High, Frances A <br />Sweetser, David A <br />Undiagnosed Diseases Network <br />Kayani, Saima <br />Snyder, Molly <br />Calvert, Sophie <br />Scheffer, Ingrid E <br />Yang, Edward <br />Waugh, Jeff L <br />Lal, Dennis <br />Bodamer, Olaf <br />Poduri, Annapurna <br />U01 HG007690/HG/NHGRI NIH HHS/United States <br />U01HG007690/GF/NIH HHS/United States <br />Fulbright Association/International <br />Bureau of Educational and Cultural Affairs of the United States Department of State and administered by the Institute of International Education/International <br />Boston Children's Hospital/International <br />K23 NS107646/NS/NINDS NIH HHS/United States <br />Australian National Health and Medical Research Council Program Grant and Practitioner Fellowship/International <br />U01 HG007942/HG/NHGRI NIH HHS/United States <br />U01HG007942/GF/NIH HHS/United States <br />Belgian American Educational Foundation/International <br />Journal Article <br />Research Support, N.I.H., Extramural <br />Research Support, Non-U.S. Gov't <br />Epilepsia. 2019 Mar;60(3):406-418. doi: 10.1111/epi.14653. Epub 2019 Jan 25. <br />