Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/20262
Title: Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region.
Authors: Kelly, McKenna;Park, Meredith;Mihalek, Ivana;Rochtus, Anne;Gramm, Marie;Pérez-Palma, Eduardo;Axeen, Erika Takle;Hung, Christina Y;Olson, Heather;Swanson, Lindsay;Anselm, Irina;Briere, Lauren C;High, Frances A;Sweetser, David A;Kayani, Saima;Snyder, Molly;Calvert, Sophie;Scheffer, Ingrid E;Yang, Edward;Waugh, Jeff L;Lal, Dennis;Bodamer, Olaf;Poduri, Annapurna
Affiliation: F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts
Neuroscience Department, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts
Dartmouth Medical School, Hanover, New Hampshire
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts
Cologne Center for Genomics, Cologne, Germany
Department of Neurology, University of Virginia, Charlottesville, Virginia
Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts
Department of Neurology, Harvard Medical School, Boston, Massachusetts
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts
Department of Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts
Department of Pediatrics, Neurology, and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas
Department of Neurology, Children's Health, Dallas, Texas
Department of Radiology, Boston Children's Hospital, Boston, Massachusetts
Department of Radiology, Harvard Medical School, Boston, Massachusetts
Department of Pediatrics, University of Texas Southwestern, Dallas, Texas
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts
Florey and Murdoch Children's Research Institute and Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia
Austin Health, Heidelberg, Victoria, Australia
Issue Date: 25-Jan-2019
EDate: 2019-01-25
Citation: Epilepsia 2019; online first: 25 January
Abstract: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. 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. 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. 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/20262
DOI: 10.1111/epi.14653
ORCID: 0000-0002-2311-2174
PubMed URL: 30682224
Type: Journal Article
Subjects: GNAO1
developmental and epileptic encephalopathy
mosaicism
movement disorders
Appears in Collections:Journal articles

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