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

Objective:To characterize the phenotypic spectrum associated withGNAO1vari-ants and establish genotype‐protein structure‐phenotype relationships. Methods:We evaluated the phenotypes of 14 patients withGNAO1variants, ana-lyzed their variants for potential pathogenici ty, and mapped them, along withthose in the literature, on a three‐dimensional structural protein model.Results:The 14 patients in our cohort, including one sibling pair, had 13 distinct,heterozygousGNAO1variants classified as pathogenic or likely pathogenic. Weattributed the same variant in two siblings to parental mosaicism. Patients initiallypresented with seizures beginning in the first 3 months of life (8/14), developmen-tal delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients hadhypotonia and developmental delay ranging from mild to severe. Nine had epi-lepsy, and nine had movement disorders, including dystonia, ataxia, chorea, anddyskinesia. The 13GNAO1variants in our patients are predicted to result inamino acid substitutions or deletions in the GNAO1 guanosine triphosphate(GTP)‐binding region, analogous to those in previous publications. Patients withvariants affecting amino acids 207‐221 had only movement disorder andhypotonia. Patients with variants affecting the C‐terminal region had the mildestphenotypes.Significance:GNAO1encephalopathy most frequently presents with seizuresbeginning in the first 3 months of life. Concurrent movement disorders are also aprominent feature in the spectrum ofGNAO1encephalopathy. All variantsaffected the GTP‐binding domain of GNAO1, highlighting the importance of thisregion for G‐protein signaling and neurodevelopment

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

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.status: publishe

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

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.