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

Undiagnosed Diseases Network

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
JournalEpilepsia
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Guanosine
Movement Disorders
Muscle Hypotonia
Brain Diseases
Guanosine Triphosphate
Phenotype
Siblings
Seizures
Chorea
Mosaicism
Dystonia
Structural Models
Dyskinesias
Amino Acid Substitution
Ataxia
GTP-Binding Proteins
Virulence
Epilepsy
Proteins
Genotype

Keywords

  • developmental and epileptic encephalopathy
  • GNAO1
  • mosaicism
  • movement disorders

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region. / Undiagnosed Diseases Network.

In: Epilepsia, 01.01.2019.

Research output: Contribution to journalArticle

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title = "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.",
keywords = "developmental and epileptic encephalopathy, GNAO1, mosaicism, movement disorders",
author = "{Undiagnosed Diseases Network} and McKenna Kelly and Meredith Park and Ivana Mihalek and Anne Rochtus and Marie Gramm and Eduardo P{\'e}rez-Palma and Axeen, {Erika Takle} and Hung, {Christina Y.} and Heather Olson and Lindsay Swanson and Irina Anselm and Briere, {Lauren C.} and High, {Frances A.} and Sweetser, {David A.} and Kayani, {Saima N} and Molly Snyder and Sophie Calvert and Scheffer, {Ingrid E.} and Edward Yang and Waugh, {Jeff L} and Dennis Lal and Olaf Bodamer and Annapurna Poduri",
year = "2019",
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AU - Undiagnosed Diseases Network

AU - Kelly, McKenna

AU - Park, Meredith

AU - Mihalek, Ivana

AU - Rochtus, Anne

AU - Gramm, Marie

AU - Pérez-Palma, Eduardo

AU - Axeen, Erika Takle

AU - Hung, Christina Y.

AU - Olson, Heather

AU - Swanson, Lindsay

AU - Anselm, Irina

AU - Briere, Lauren C.

AU - High, Frances A.

AU - Sweetser, David A.

AU - Kayani, Saima N

AU - Snyder, Molly

AU - Calvert, Sophie

AU - Scheffer, Ingrid E.

AU - Yang, Edward

AU - Waugh, Jeff L

AU - Lal, Dennis

AU - Bodamer, Olaf

AU - Poduri, Annapurna

PY - 2019/1/1

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N2 - 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.

AB - 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.

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KW - movement disorders

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